Method for treating diabetic nephropathy

ABSTRACT

Provided, among other things, is a method of treating or ameliorating or preventing an indication of the invention in an animal, including a human comprising administering an effective amount of a compound of the formula I:

This patent application is a divisional application of U.S. patentapplication Ser. No. 10/873,056, filed Jun. 21, 2004, which is acontinuation of U.S. patent application Ser. No. 09/905,188, filed Jul.13, 2001, which claims the benefit of U.S. Ser. No. 60/296,435, filedJun. 6, 2001; U.S. Ser. No. 60/259,431, filed Dec. 29, 2000; U.S. Ser.No. 60/259,242, filed Jan. 2, 2001; U.S. Ser. No. 60/218,273, filed Jul.13, 2000, each of which is incorporated herein by reference in itsentirety.

The present invention relates to methods for treating certain fibroticdiseases or other indications.

Glucose and other sugars react with proteins by a non-enzymatic,post-translational modification process called non-enzymaticglycosylation. At least a portion of the resulting sugar-derivedadducts, called advanced glycosylation end products (AGEs), mature to amolecular species that is very reactive, and can readily bind to aminogroups on adjacent proteins, resulting in the formation of AGEcross-links between proteins. Recently a number of classes of compoundshave been identified whose members inhibit the formation of thecross-links, or in some cases break the cross-links. These compoundsinclude, for example, the thiazolium compounds described in U.S. Pat.No. 5,853,703. As AGEs, and particularly the resulting cross-links, arelinked to several degradations in body function linked with diabetes orage, these compounds have been used, with success, in animal models forsuch indications. These indications include loss of elasticity in bloodvasculature, loss of kidney function and retinopathy.

Now, as part of studies on these compounds, it has been identified thatthese compounds inhibit the formation of bioactive agents, such asgrowth factors and inflammatory mediators, that are associated with anumber of indications. These agents include vascular endothelial growthfactor (VEGF) and TGF[beta]. As a result, a number of new indicationshave been identified for treatment with agents that inhibit theformation of, or more preferably break, AGE-mediated cross-links. It isnot unreasonable to infer that the effects seen are due to the removalof AGE-related molecules that provide a stimulus for the production orrelease of these growth factors. Removal of such molecules is believedto proceed in part due to the elimination of AGE-related cross-linksthat lock the AGE-modified proteins in place. Moreover, such compoundsalso reduce the expression of collagen in conditions associated withexcess collagen production. Regardless of the mechanism, now providedare new methods of treating a number of indications.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a method of treating orameliorating or preventing an indication of the invention in an animal,including a human comprising administering an effective amount of acompound of the formula I:

wherein the substituent groups are defined below. The invention alsorelates to compounds of formula I.

The compounds used in the methods described here are first agents, whichare those described with reference to formula I, or second agents, whichare aminoguanidine or those compounds described with reference toformula I. The second agents can be used as an adjunct to treatment witha first agent, or as the primary effective agent where noted.

Second agents are aminoguanidine or a compound of the aminoguanidineclass of formula A

wherein R is an alkyl group, or a group of the formula —N(R⁴)(R⁵)wherein R⁴ is hydrogen, and R⁵ is an alkyl group or a hydroxyalkylgroup; or R⁴ and R⁵ together with the nitrogen atom are a heterocyclicgroup containing 4-6 carbon atoms and, in addition to the nitrogen atom,0-1 oxygen, nitrogen or sulfur atoms; R¹ is hydrogen or an amino group;R² is hydrogen or an amino group; R³ is hydrogen or an alkyl group,wherein R and R¹ cannot both be amino groups. Preferably at least one ofR¹, R², and R³ is other than hydrogen. The compounds can be used astheir pharmaceutically acceptable acid addition salts, and mixtures ofsuch compounds. When aminoguanidine compounds are administered, they canbe administered by any route of pharmaceutical administration includingthose discussed below for other first agents.

DETAILED DESCRIPTION OF THE INVENTION

Provided is a method of treating or ameliorating an indication of theinvention in an animal, including a human, comprising administering aneffective amount of (A) a compound of the formula I:

wherein

a. R¹ and R² are

-   -   1. independently selected from hydrogen, acylamino,        acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy,        alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino,        (C₁-C₃)alkylenedioxy, allyl, amino, ω-alkylenesulfonic acid,        carbamoyl, carboxy, carboxyalkyl, cycloalkyl, dialkylamino,        halo, hydroxy, (C₂-C₆)hydroxyalkyl, mercapto, nitro, sulfamoyl,        sulfonic acid, alkylsulfonyl, alkylsulfinyl, alkylthio,        trifluoromethyl, azetidin-1-yl, morpholin-4-yl,        thiomorpholin-4-yl, piperidin-1-yl, 4-[C₆ or        C₁₀]arylpiperidin-1-yl, 4-[C₆ or C₁₀]arylpiperazin-1-yl, Ar        {wherein, consistent with the rules of aromaticity, Ar is C₆ or        C₁₀ aryl or a 5- or 6-membered heteroaryl ring, wherein        6-membered heteroaryl ring contains one to three atoms of N, and        the 5-membered heteroaryl ring contains from one to three atoms        of N or one atom of O or S and zero to two atoms of N, each        heteroaryl ring can be fused to a benzene, pyridine, pyrimidine,        pyridazine, pyrazine, or (1,2,3)triazine (wherein the ring        fusion is at a carbon-carbon double bond of Ar)}, Ar-alkyl,        Ar—O, ArSO₂—, ArSO—, ArS—, ArSO₂NH—, ArNH, (N—Ar)(N-alkyl)N—,        ArC(O)—, ArC(O)NH—, ArNH—C(O)—, and (N—Ar)(N-alkyl)N—C(O)—, or        together R₁ and R₂ comprise methylenedioxy [in one embodiment,        independently selected from hydrogen, acylamino, acyloxyalkyl,        alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl,        alkoxycarbonylalkyl, alkyl, (C₁-C₃)alkylenedioxy, allyl,        ω-alkylenesulfonic acid, carbamoyl, carboxy, carboxyalkyl,        cycloalkyl, halo, hydroxy, (C₂-C₆)hydroxyalkyl, mercapto, nitro,        sulfamoyl, sulfonic acid, alkylsulfonyl, alkylsulfinyl,        alkylthio, trifluoromethyl, Ar {wherein, consistent with the        rules of aromaticity, Ar is C₆ or C₁₀ aryl or a 5- or 6-membered        heteroaryl ring, wherein 6-membered heteroaryl ring contains one        to three atoms of N, and the 5-membered heteroaryl ring contains        from one to three atoms of N or one atom of O or S and zero to        two atoms of N, each heteroaryl ring can be fused to a benzene,        pyrimidine, pyridazine, pyrazine, or (1,2,3)triazine (wherein        the ring fusion is at a carbon-carbon double bond of Ar)},        Ar-alkyl, Ar—O, ArSO₂—, ArSO—, ArS—, ArSO₂NH—, ArNH,        (N—Ar)(N-alkyl)N—, ArC(O)—, ArC(O)NH—, ArNH—C(O)—, and        (N—Ar)(N-alkyl)N—C(O)—]; or    -   2. together with their ring carbons form a C₆- or C₁₀-aromatic        fused ring system; or    -   3. together with their ring carbons form a C₅-C₇ fused        cycloalkyl ring having up to two double bonds including the        fused double bond of the -olium or -onium containing ring, which        cycloalkyl ring can be substituted by one or more of the group        consisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl,        carboxy, fluoro, or oxo substituents [in one embodiment,        together with their ring carbons form a C₅-C₇ fused cycloalkyl        ring having up to two double bonds including the fused double        bond of the -olium or -onium containing ring, which cycloalkyl        ring can be substituted by one or more of the group consisting        of alkyl, alkoxycarbonyl, aminocarbonyl, carboxy, fluoro, or oxo        substituents]; or    -   4. together with their ring carbons form a 5- or 6-membered        heteroaryl ring, wherein the 6-membered heteroaryl ring contains        one to three atoms of N, and the 5-membered heteroaryl ring        contains from one to three atoms of N or one atom of O or S and        zero to two atoms of N, each heteroaryl ring may be optionally        substituted with one or more 1-pyrrolidinyl-, 4-[C₆ or        C₁₀]arylpiperazin-1-yl, 4-[C₆ or C₁₀]arylpiperidin-1-yl,        azetidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl,        piperidin-1-yl, halo or (C₁-C₃)alkylenedioxy groups [in one        embodiment, together with their ring carbons form a 5- or        6-membered heteroaryl ring, wherein the 6-membered heteroaryl        ring contains one to three atoms of N, and the 5-membered        heteroaryl ring contains from one to three atoms of N or one        atom of O or S and zero to two atoms of N, each heteroaryl ring        may be optionally substituted with one or more halo or        (C₁-C₃)alkylenedioxy groups]; or    -   5. together with their ring carbons form a five to eight        membered heterocycle, wherein the heterocycle consists of ring        atoms selected from the group consisting of carbon, nitrogen,        and S(O)_(n), where n=0, 1, or 2;        b. Z is    -   1. hydrogen, alkyl, Ar—CH₂;    -   2. a group of the formula —NR³R⁴, wherein R³ and R⁴ may be        independently hydrogen, alkyl, Ar, or Ar-alkyl-;    -   3. a group of the formula —CH(OR¹¹)R¹², wherein R¹¹ is hydrogen,        methyl, ethyl or CH₃C(O)—; and R¹² is [C₁ to C₆]alkyl, Ar, or        CO₂R¹³ wherein R¹³ is hydrogen methyl or ethyl;    -   4. a group of the formula —C(CO₂R¹³)(OR¹¹)R¹²    -   5. a group of the formula —CH₂WAr, wherein W is —(C═O)— or        —S(O)_(n)— where n=1 or 2; or    -   6. a group of the formula —CH₂C═C—R¹⁴, wherein R¹⁴ is        (C₁-C₆)alkyl;        c. Y is    -   1. amino, or    -   2. a group of the formula —CH(R⁵)—R⁶ wherein        -   (a) R⁵ is hydrogen, alkyl-, cycloalkyl-, alkenyl-, alkynyl-,            aminoalkyl-, dialkylaminoalkyl-, (N—[C₆ or            C₁₀]aryl)(N-alkyl)aminoalkyl-, piperidin-1-ylalkyl-,            1-pyrrolidinylalkyl, azetidinylalkyl,            4-alkylpiperazin-1-ylalkyl, 4-alkylpiperidin-1-ylalkyl,            4-[C₆ or C₁₀]arylpiperazin-1-ylalkyl, 4-[C₆ or            C₁₀]arylpiperidin-1-ylalkyl, azetidin-1-ylalkyl,            morpholin-4-ylalkyl, thiomorpholin-4-ylalkyl,            piperidin-1-ylalkyl, [C₆ or C₁₀C]aryl, or independently the            same as R⁶ [in one embodiment, hydrogen or alkyl];        -   (b) R⁶ is            -   (1) hydrogen, alkyl (which can be substituted by                alkoxycarbonyl), alkenyl, alkynyl, cyano- or Rs, wherein                Rs is a C₆ or C₁₀ aryl or a heterocycle containing 4-10                ring atoms of which 1-3 are heteroatoms selected from                the group consisting of oxygen, nitrogen and sulfur; or            -   (2) a group of the formula —W—R⁷, wherein R⁷ is alkyl,                alkoxy, hydroxy or Rs, wherein W is —C(═O)— or                —S(O)_(n)— where n=1 or 2;            -   (3) a group of the formula —W—OR⁸ wherein R⁸ is hydrogen                or alkyl,            -   (4) a group of the formula —CH(OH)Rs; or            -   (5) a group of the formula —W—N(R⁹)R¹⁰, wherein                -   [a] R⁹ is hydrogen and R¹⁰ is an alkyl or                    cycloalkyl, optionally substituted by                -    (i) [C₆ or C₁₀]aryl, or                -    (ii) a 5- or 6-membered heteroaryl ring, wherein                    the 6-membered heteroaryl ring contains one to three                    atoms of N, and the 5-membered heteroaryl ring                    contains from one to three atoms of N or one atom of                    O or S and zero to two atoms of N, said heteroaryl                    ring can be optionally substituted with one or more                    1-pyrrolidinyl, 4-[C₆ or C₁₀]arylpiperazin-1-yl,                    4-[C₆ or C₁₀]arylpiperidin-1-yl, azetidin-1-yl, and                    morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl,                    halo or (C₁-C₃)alkylenedioxy groups, or fused to a                    substituted phenyl or pyridine ring, wherein the                    ring fusion is at a carbon-carbon double bond of the                    heteroaryl ring [in one embodiment, a 5- or                    6-membered heteroaryl ring, wherein the 6-membered                    heteroaryl ring contains one to three atoms of N,                    and the 5-membered heteroaryl ring contains from one                    to three atoms of N or one atom of O or S and zero                    to two atoms of N, said heteroaryl ring can be                    optionally substituted with one or more halo or                    (C₁-C₃)alkylenedioxy groups, or fused to a                    substituted phenyl], or                -    (iii) a heterocycle containing 4-10 ring atoms of                    which 1-3 are heteroatoms selected from the group                    consisting of oxygen, nitrogen and sulfur; or                -   [b] R⁹ is hydrogen or lower alkyl and R¹⁰ is Ar; or                -   [c] R⁹ is hydrogen or lower alkyl, and R¹⁰ is a                    heterocycle containing 4-10 ring atoms of which 1-3                    are heteroatoms are selected from the group                    consisting of oxygen, nitrogen and sulfur, said                    heterocycle; or                -   [d] R⁹ and R¹⁰ are both alkyl groups; or                -   [e] R⁹ and R¹⁰ together with N form a heterocycle                    containing 4-10 ring atoms which can incorporate up                    to one additional heteroatom selected from the group                    of N, O or S in the ring, wherein the heterocycle is                    optionally substituted with (C₆- or C₁₀)aryl, (C₆-                    or C₁₀)arylalkyl, or a 5- or 6-membered heteroaryl                    ring, wherein the 6-membered heteroaryl ring                    contains one to three atoms of N, and the 5-membered                    heteroaryl ring contains from one to three atoms of                    N or one atom of O or S and zero to two atoms of N,                    each such heteroaryl can be optionally substituted                    with one or more 1-pyrrolidinyl, 4-[C₆ or                    C₁₀]arylpiperazin-1-yl, 4-[C₆ or                    C₁₀]arylpiperidin-1-yl, azetidin-1-yl,                    morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl,                    halo or (C₁-C₃)alkylenedioxy [in one embodiment, R⁹                    and R¹⁰ together with N form a heterocycle                    containing 4-10 ring atoms which can incorporate up                    to one additional heteroatom selected from the group                    of N, O or S in the ring, wherein the heterocycle is                    optionally substituted with (C₆- or C₁₀)aryl, (C₆-                    or C₁₀)arylalkyl, or a 5- or 6-membered heteroaryl                    ring, wherein the 6-membered heteroaryl ring                    contains one to three atoms of N, and the 5-membered                    heteroaryl ring contains from one to three atoms of                    N or one atom of O or S and zero to two atoms of N,                    each such heteroaryl can be optionally substituted                    with one or more halo or (C₁-C₃)alkylenedioxy]; or                -   [f] R⁹ and R¹⁰ are both hydrogen; or                    d. Q is N, O or S;                    e. M is absent when Q is O or S;                    f. M is alkyl, vinyl or allyl, or independently the                    same as Y; and                    g. X is a pharmaceutically acceptable anion, or                    (B) a pharmaceutically acceptable salt of the                    compound,

-   wherein aryl or Ar can be substituted with, in addition to any    substitutions specifically noted, one or more substituents selected    from the group consisting of acylamino, acyloxyalkyl, alkanoyl,    alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl,    alkyl, alkylamino, (C₁-C₃)alkylenedioxy, alkylsulfonyl,    alkylsulfinyl, ω-alkylenesulfonic acid, alkylthio, allyl, amino,    ArC(O)—, ArC(O)NH—, ArO—, Ar—, Ar-alkyl-, carboxy, carboxyalkyl,    cycloalkyl, dialkylamino, halo, trifluoromethyl, hydroxy,    (C₂-C₆)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid,    1-pyrrolidinyl, 4-[C₆ or C₁₀]arylpiperazin-1-yl-, 4-[C₆ or    C₁₀]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl,    thiomorpholin-4-yl, piperidin-1-yl [in one embodiment, aryl or Ar    can be substituted with, in addition to any substitutions    specifically noted, one or more substituents selected from the group    consisting of acylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl,    alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,    (C₁-C₃)alkylenedioxy, alkylsulfonyl, alkylsulfinyl,    ω-alkylenesulfonic acid, alkylthio, allyl, ArC(O)—, ArC(O)NH—, ArO—,    Ar—, Ar-alkyl-, carboxy, carboxyalkyl, cycloalkyl, halo,    trifluoromethyl, hydroxy, (C₂-C₆)hydroxyalkyl, mercapto, nitro,    sulfamoyl, sulfonic acid]; and

-   wherein heterocycles, except those of Ar, can be substituted with,    in addition to any substitutions specifically noted, acylamino,    alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,    alkylamino, alkylsulfonyl, alkylsulfinyl, alkylthio, amino, ArC(O)—,    ArO—, Ar—, carboxy, dialkylamino, fluoro, fluoroalkyl,    difluoroalkyl, hydroxy, mercapto, sulfamoyl, or trifluoromethyl [in    one embodiment, heterocycles, except those of Ar, can be substituted    with, in addition to any substitutions specifically noted,    acylamino, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl,    alkyl, alkylsulfonyl, alkylsulfinyl, alkylthio, ArC(O)—, ArO—, Ar—,    carboxy, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto,    sulfamoyl, or trifluoromethyl].

In one embodiment, the compound of formula I, is that wherein Y isaccording to formula —CH(R⁵)R⁶. In another embodiment, the compound offormula I, is that of formula I, wherein Y is according to formula—CH(R⁵)—W—R⁷. In another embodiment, the compound of formula I, is thatof formula I, wherein Y is according to formula —CH(R⁵)—W—Rs. In anotherembodiment, the compound of formula I, is that of formula I, wherein R¹and R² together with their ring carbons form a C₆- or C₁₀-aromatic fusedring which can be substituted by one or more halo, amino, alkyl,sulfonic acid, alkylsulfonyl or ω-alkylenesulfonic acid groups, or aC₁-C₃ alkylenedioxy group with the proviso that when Q is nitrogen R¹and R² do not form a C₆ fused aromatic ring. In another embodiment, thecompound of formula I, is that of the compound of formula I, wherein Qis S, and Y and Z are both —NH₂.

Certain Fibrotic Diseases

Among the indications that can be treated with the invention are anumber of indications linked to or associated with the formation ofexcess collagen. Among these, a number of the indications can be termedfibrotic diseases.

Such fibrotic diseases include systemic sclerosis, mixed connectivetissue disease, fibrodysplasia, fibrocystic disease; sarcoidosis,myositis (e.g. polymyositis, primary idiopathic polymyositis, childhoodpolymyositis, dermatomyositis, childhood dermatomyositis, primaryidiopathic dermatomyositis in adults, inclusion body myositis,polymyositis or dermatomyositis associated with malignant tumors).Dermatomyositis can be associated with fibrosing or hypertrophicaspects, including fibrosing alveolitis and pulmonary fibrosis.Treatment using the invention is expected to treat, prevent, reduce orameliorate such diseases or hypertrophy, fibrotic hypertrophy orfibrosis in such diseases. Amelioration includes reducing the rate ofprogression of a disease.

Among these fibrotic diseases are diseases that have as a manifestationfibrotic vascular intimal hypertrophy. These diseases include vasculitis(including coronary artery vasculitis), polyarteritis nodosa or temporalarteritis. Treatment using the invention is expected to treat, prevent,reduce or ameliorate vascular intimal hypertrophy in such diseases.

These fibrotic diseases further include diseases that have as amanifestation fibrotic hypertrophy of skin and/or muscle tissue. Thesediseases include scleroderma, eosinophilic fasciitis, discoid lesionsassociated with lupus or discoid lupus or surgical adhesions. Treatmentusing the invention is expected to treat, prevent, reduce or amelioratesuch indications or hypertrophy or fibrosis of skin or muscle tissue.

Such fibrotic diseases further include diseases that have as amanifestation fibrotic hypertrophy of nerve tissue. These diseasesinclude cerebrosclerosis, annular sclerosis. diffuse sclerosis and lobarsclerosis. Treatment using the invention is expected to treat, prevent,reduce or ameliorate such diseases, or hypertrophy, fibrotic hypertrophyor fibrosis of nerve tissue in such diseases.

These fibrotic diseases further include fibrotic lung diseases that haveas a manifestation fibrotic hypertrophy or fibrosis of lung tissue.These diseases include pulmonary fibrosis (or interstitial lung diseaseor interstitial pulmonary fibrosis), idiopathic pulmonary fibrosis, thefibrotic element of pneumoconiosis (which is associated with exposure toenvironmental hazards such as smoking, asbestos, cotton lint, stonedust, mine dust and other particles), pulmonary sarcoidosis, fibrosingalveolitis, the fibrotic or hypertrophic element of cystic fibrosis,chronic obstructive pulmonary disease, adult respiratory distresssyndrome and emphysema Treatment using the invention is expected totreat, prevent, reduce or ameliorate such diseases, or hypertrophy,fibrotic hypertrophy or fibrosis in such diseases.

Such fibrotic diseases further include diseases that have as amanifestation fibrotic hypertrophy or fibrosis of prostate, liver, thepleura (e.g., pleurisy, pleural fibrosis) or pancreas. These diseasesinclude benign prostatic hypertrophy (BPH) and fibrosis of the liver.Treatment using the invention is expected to treat, prevent, reduce orameliorate such diseases, or hypertrophy, fibrotic hypertrophy orfibrosis in such diseases.

These fibrotic diseases further include diseases that have as amanifestation fibrotic hypertrophy or fibrosis of the bowel wall, suchas inflammatory bowel disease, including Crohn's disease. Treatmentusing the invention is expected to treat, prevent, reduce or amelioratesuch diseases, or hypertrophy, fibrotic hypertrophy or fibrosis in suchdiseases.

Arteriosclerosis, Atherosclerosis, Stiff Vessel Disease, PeripheralVascular Disease, Coronary Heart Disease, Stroke, Myocardial Infarct,Cardiomyopathies, Restenosis

Arteriosclerosis is a disease marked by thickening, hardening, and lossof elasticity in arterial walls, of which atherosclerosis is a sub-type.Arteriosclerosis in turn falls within the genus of stiff vesseldiseases. Without limitation to theory, it is believed that damage tothe blood vessels of these diseases is due to AGE-caused damage, eitherthrough protein cross-linking or the stimulation of bioactive agents, orboth. Accordingly, the first agents are used to treat, prevent, reduceor ameliorate stiff vessel disease, including arteriosclerosis andatherosclerosis. Peripheral vascular disease is an indication thatoverlaps with atherosclerosis but also covers disease which is believedto have a stronger inflammatory component. First agents are used totreat, prevent, reduce or ameliorate peripheral vascular disease.Coronary heart disease is a form of atherosclerosis of the coronaryarteries. First agents are used to treat, prevent, reduce or amelioratecoronary heart disease.

When the heart pumps blood into the vascular system, the ability of thearteries to expand helps to push blood through the body. When arteriesbecome stiff, as they do in the natural process of aging, the ability ofthe arteries to expand is diminished and also has consequences for theheart. The heart has to work harder to pump the blood into the stiffarteries, and eventually hypertrophies (enlarges in size) to accomplishthis. A hypertrophied heart is an inefficient pump, and is one of thedisorders that leads to congestive heart failure. One compound believedto work by a mechanism shared by the compounds of the invention,3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt, showed an abilityto reverse the stiffness of arteries in a Phase IIa clinical trial, asmeasured by the ratio of stroke volume (ml) to pulse pressure (mm Hg).The potential clinical benefit of this is to lessen the effort that theheart must expend to push blood throughout the body. The effect is alsobelieved to contribute to preventing hypertrophy and subsequentinefficiency of the heart, which inefficiency would contribute tocongestive heart failure.

Stroke is a cardiovascular disease that occurs when blood vesselssupplying blood (oxygen and nutrients) to the brain burst or areobstructed by a blood clot or other particle. Nerve cells in theaffected area of the brain die within minutes of oxygen deprivation andloss of nerve cell function is followed by loss of corresponding bodilyfunction. Of the four main types of stroke, two are caused by bloodclots or other particles. The former two are the most common forms ofstroke, accounting for about 70-80 percent of all strokes.

Blood clots usually form in arteries damaged by atherosclerosis. Whenplaque tears from the sheer forces of blood flowing over an uneven,rigid cap atop the plaque site, thrombotic processes become involved atthe “injury” site. As a result, clots can form. First agents are used toprevent, reduce or ameliorate the risk of stroke in patients who havesuffered previous strokes or have otherwise been identified as at risk.

First agents can also be used to treat, prevent, reduce or ameliorateperipheral vascular disease and periarticular rigidity.

Treatment with the first agents during the relatively immediateaftermath of a heart attack can be used to reduce the size of themyocardial infarct resulting from the heart attack. This treatment ispreferably administered within six hours of the heart attack, morepreferably, within three hours. While the dosages discussed below can beused with this indication, such as a dose of 0.01-4.0 mg/kg administeredorally or 0.01-2.0 mg/kg administered intravenously, preferably withinthe time period outlined above. Preferred routes of administrationinclude i.v. injection or i.v. drip. Thereafter, optional supplementaladministrations can be made with the dosages described below.

Atherosclerosis is a disease that involves deposition of blood lipids inplaque in the arteries throughout the body. In coronary arteries,accumulation of plaque progressively leads to reduced coronary flow,with occlusion of the arteries causing focal death of cardiac tissue(myocardial infarction, heart attack). If the amount of tissue that diesis large enough, death ensures. In a Phase IIa trial, one compoundbelieved to work by a mechanism shared by the compounds of theinvention, 3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt,increased the amount of circulating triglycerides (lipids). Consistentwith the known presence of AGEs in plaque, the result indicates that theagent had a lipid mobilizing effect on arterial plaque. Reducing localdeposits of plaque should eventually lessen the risk of myocardialinfarction and death due to heart attacks.

Fibrotic diseases further include diseases that have as a manifestationfibrotic hypertrophy of the heart. These diseases include endomyocardialfibrosis (wherein endocardium and subendocardium are fibrosed, such asin some manifestations of restrictive cardiomyopathy), dilatedcongestive cardiomyopathy (a disorder of myocardial function with heartfailure in which ventricular dilation and systolic dysfunctionpredominate), hypertrophic cardiomyopathy (characterized by markedventricular hypertrophy with diastolic dysfunction in the absence of anafterload demand), and other cardio-hypertrophies. In dilated congestivecardiomyopathy, typically at presentation there is chronic myocardialfibrosis with diffuse loss of myocytes. In hypertrophic cardiomyopathy,usually the interventricular septum is hypertrophied more than the leftventricular posterior wall (asymmetric septal hypertrophy). Treatmentusing the invention is expected to treat, prevent, reduce or amelioratesuch diseases, or hypertrophy, fibrotic hypertrophy or fibrosis in suchdiseases.

Hypertrophies of the heart can be diagnosed and monitored by methodsknown in the art, such as by electrocardiogram, echocardiography ormagnetic resonance imaging. Such diagnostic methods can be applied inparticular for subjects having a risk factor for such hypertrophy, suchas congestive heart failure, prior cardiac surgery or diabetes. In oneaspect, the invention comprises identifying cardio-hypertrophy withusing biophysical diagnostic tools, and administering an active agent ofthe invention to treat, prevent, reduce or ameliorate such diseases, orhypertrophy, fibrotic hypertrophy or fibrosis in such diseases. Theinvention can further include monitoring cardio-hypertrophy during thecourse of treatment with active agent.

Erosion or tearing of arterial wall plaque can occur due to the roughand irregular shape of the plaque as it forms from deposition of lipidsand invasion of cells such as monocytes and macrophages (foam cells).When erosion occurs platelets and other components of the blood clottingsystem are activated, resulting in formation of a clot (thrombus). Whenthe thrombus grows to such as state that blood flow is reduced, severeangina attacks that characterize unstable angina can occur. Plaque formsirregular shapes and in doing so creates shear stresses from the flow ofblood over this irregular form. It is the irregularity of plaque shapethat leads to the dislodging or tearing of the plaque, and to thesubsequent invasion of reactive cells. On the surface of plaque iscollagen, which is believed to contribute to the rigidity of theirregular shape. Without limitation to theory, it is believed thatreducing the crosslinking of such a rigid collagen cap results insmoother blood flow, with a reduced risk of angina-causing tears.Accordingly, first agents are used to treat, prevent, reduce orameliorate unstable angina.

Faithful conduction of the electrical impulse from the sinoatrial to theatrioventricular nodes depends upon close apposition of myocardialcells. Excess production of collagen in the heart, which occursnaturally with aging but more so in diabetes and in conditions of heartdisorders such as hypertension, causes an increase in the distancebetween myocardial cells, leading to atrial fibrillation. First agentsare used to treat, prevent, reduce or ameliorate atrial fibrillation.

The fibrotic indications further include restenosis, which is theprocess of increasing artery closure following an operation to open theartery, such as balloon angioplasty.

Bladder Elasticity

Indications that can be treated, prevented, reduced or ameliorated withthe first agents include loss of bladder elasticity. Bladder elasticityis tied to the frequency of urination, and the urgency of desire tourinate. Accordingly, the invention can be used to treat, prevent,reduce or ameliorate non-obstructive uropathy, a disorder characterizedby an overactive bladder that entails increased frequency of urination,a strong and sudden desire to urinate (urgency) which may also beassociated with involuntary urinary leakage (urge incontinence).

Macular Degeneration

The effect of the first agents in reducing levels of other endogenousbioactive agents, particularly VEGF and/or TGF[beta], is believed tounderlie effectiveness against macular degeneration or macular edema.Again, however, the invention is not limited to theory. Moreover, aanti-fibrotic effect or another effect against tissue hypertrophy maycontribute. Treatment using the invention is expected to treat, prevent,reduce or ameliorate macular degeneration or macular edema. In oneaspect of the invention, the treatment is used to treat, prevent, reduceor ameliorate the wet form of macular degeneration. In the wet form, newblood vessel growth has a greater contribution to the disease.

Amyotrophic Lateral Sclerosis (ALS)

ALS is associated with degradations of the motor neuron system and/orthe posterior column of the spinal cord. In ALS patients, thesestructures tend to stain with AGE-reactive antibodies. Treatment usingthe invention is expected to treat, prevent, reduce or ameliorate ALS.

Rheumatoid Arthritis, Osteoarthritis, Bone Resorption

It is believed, without limitation to such theory, that reducing AGEaccumulation at the joints affected by rheumatoid arthritis orosteoarthritis reduces stimulation of the production of cytokinesinvolved in inflammatory processes of the disease. Treatment using theinvention is expected to treat, prevent, reduce or ameliorate rheumatoidarthritis or osteoarthritis. Similarly, it is believed that reducing AGEaccumulation at bone reduces stimulation of bone resorption.Accordingly, the invention is used to treat, prevent, reduce orameliorate osteoporosis, bone loss or brittle bone.

Dialysis

The first agents can be administered as part of a dialysis exchangefluid, thereby preventing, limiting or ameliorating the damage to tissuecaused by the sugars found in such exchange fluid. For example, firstagents are expected to prevent, limit or ameliorate the stiffening andsclerosing of peritoneal tissue that occurs in peritoneal dialysis, aswell as prevent, limit or ameliorate the formation of new blood vesselsin the peritoneal membrane. In hemodialysis, first agents are expectedto prevent, limit or ameliorate the stiffening and sclerosing of redblood cells and vasculature resulting from exposure to the sugarsexchanged into the blood during dialysis. Exchange fluids for peritonealdialysis typically contain 10-45 g/L of reducing sugar, typically 25g/L, which causes the formation of AGEs and consequent stiffening anddegradation of peritoneal tissue. Similarly, hemodialysis fluidstypically contain up to about 2.7 μL of reducing sugar, typically 1 to1.8 g/L. Thus, the invention provides methods by which the first agentsare provided in these fluids and thereby prevent, limit or amelioratethe damage that would otherwise result. Alternatively, the inventionprovides methods whereby the first agents are administered by themethods described below to prevent, limit or ameliorate such damage fromdialysis. In hemodialysis, the exchange fluid preferably contains0.006-2.3 mg/L of an agent of the invention, more preferably, 0.06 to1.0 mg/L. In peritoneal dialysis, the exchange fluid preferably contains0.01 to 24 mg/L of an agent of the invention, or preferably, 1.0 to 10mg/L.

In one embodiment, preventing or ameliorating is effected with a secondagent. A preferred route of administration is inclusion in the dialysisfluids. In hemodialysis, the exchange fluid preferably contains 0.125 to2.5 mg/L of aminoguanidine, more preferably, 0.2 to 1.0 mg/L. Inperitoneal dialysis, the exchange fluid preferably contains 1.25 to 25mg/L of aminoguanidine, or preferably, 2.0 to 10 mg/L. In a preferredaspect of the invention, the first agents are initially administered,and subsequently second agents are used to moderate or limit damagethereafter.

Asthma

It is believed, without limitation to such theory, that the first agentsor second agents act to prevent, reduce or ameliorate the small butsignificant thickening of the lung airways associated with asthma.Moreover, the agents are believed to reduce stimulation of theproduction of cytokines involved in inflammatory processes of thedisease. Accordingly, the agents are used to treat, prevent, reduce orameliorate asthma. In this embodiment, one preferred route ofadministration is pulmonary, such as via an aerosol, though peroraladministration is also preferred.

Carpal Tunnel Syndrome

It is believed, without limitation to such theory, that the first agentsact to prevent, reduce or ameliorate fibrotic and cytokine-inducedelements of carpal tunnel syndrome. Accordingly, the first agents areused to treat, prevent, reduce or ameliorate carpal tunnel syndrome.

Fibrotic diseases also include Dupuytren's contracture, a contracture ofthe palmar fascia often causing the ring and little fingers to bend intothe palm. Treatment using the invention is expected to treat, prevent,reduce or ameliorate Dupuytren's contracture, or hypertrophy, fibrotichypertrophy or fibrosis in Dupuytren's contracture.

In these embodiments, one preferred route of administration is localinjection.

Periodontal Disease

The incidence of periodontal disease is higher in subjects with eitherinsulin-deficient or insulin-resistant diabetes, with consequenthyperglycemia. Again, without limitation to such theory, it is believedthat the first agents act to prevent, reduce or ameliorate AGE-inducedcytokine action to create or exacerbate periodontal disease.Accordingly, the first or second agents are used to treat, prevent,reduce or ameliorate periodontal disease. In this embodiment, onepreferred primary or supplemental route of administration is viamouthwash, or compositions adapted for delivery into the subgingivalperiodontal pocket (such as implants and erodible microspheres). Peroraladministration is again useful. The mouthwash preferably contains0.003-1.0 mg/L of a first agent, more preferably, 0.01-0.1 mg/L.

Sickle Cell Anemia

It is believed, without limitation to such theory, that the first agentsact to prevent, reduce or ameliorate the restraint on blood flow causedby sickling. Again without limitation to theory, the mode of action isbelieved to be in reducing vascular as well as blood cell inelasticity.Accordingly, the first agents are used to treat, prevent, reduce orameliorate a sickle cell anemia.

Erectile Dysfunction

Fibrotic diseases further include diseases that have as a manifestationfibrotic disease of the penis, including Peyronie's disease (fibrosis ofthe cavernous sheaths leading to contracture of the investing fascia ofthe corpora, resulting in a deviated and painful erection). Treatmentusing the invention is expected to treat, prevent, reduce or amelioratesuch diseases, or hypertrophy, fibrotic hypertrophy or fibrosis in suchdiseases.

Without limitation to theory, it is believed that the first agents actto prevent, reduce or ameliorate inelasticity of tissue of the penisand/or fibrosis of tissue of the penis, such as inelasticity or fibrosisof the cavernous sheaths leading to contracture of the investing fasciaof the corpora. At least partial restoration of the resultinginelasticity is believed to facilitate engorgement of the corporacavernosa with blood. Accordingly, the first agents are used to treat,prevent, reduce or ameliorate erectile dysfunction.

Limited Joint Mobility

Limited Joint Mobility (LJM) is a disorder associated with diabetes andtypically involves the joints of the hands. The fourth and fifth fingersare affected initially by limitation of motion. AGE glycation andcrosslinking of tendons (collagen) in the joints is believed tocontribute to the disease. It is believed, without limitation to theory,that the first agents act to prevent, reduce or ameliorate inelasticity,fibrous tissue or cytokine-induced inflammation associated with limitedjoint mobility. Accordingly, the first agents are used to treat,prevent, reduce or ameliorate limited joint mobility.

Antineoplastic Applications

The first agents inhibit the stimulated formation of bioactive agents,such as VEGF, associated with angiogenesis. Angiogenesis is critical forboth normal development and the growth and metastasis of solid tumors.Accordingly, the first agents are used to treat, prevent, reduce orameliorate the growth of neoplasms by limiting the formation of bloodvessels needed to sustain the neoplasms.

End Stage Renal Disease, Diabetic Nephropathy

Diabetic Nephropathy is a complication of diabetes that evolves early,typically before clinical diagnosis of diabetes is made. The earliestclinical evidence of nephropathy is the appearance of low but abnormallevels (>30 mg/day or 20 μg/min) of albumin in the urine(microalbuminuria), followed by albuminuria (>300 mg/24 h or ˜200μg/min) that develops over a period of 10-15 years. In patients withtype 1 diabetes, diabetic hypertension typically becomes manifest earlyon, by the time that patients develop microalbuminuria. Once overtnephropathy occurs, the glomerular filtration rate (GFR) falls overseveral years resulting in End Stage Renal Disease (ESRD) in 50% of type1 diabetic individuals within 10 years and in >75% of type 1 diabeticsby 20 years of onset of overt nephropathy. Albuminuria (i.e.,proteinuria) is a marker of greatly increased cardiovascular morbidityand mortality for patients with either type 1 or type 2 diabetes.

Without limitation to theory, it is believed that damage to theglomeruli and blood vessels of the kidney is due to AGE-caused damage,either through protein cross-linking or the stimulation of bioactiveagents, or both. Accordingly, the first agents are used to treat,prevent, reduce or ameliorate damage to kidney in patients at risk forESRD. The first agents can also be used to treat, prevent, reduce orameliorate glomerulosclerosis.

Hypertension, Isolated Systolic Hypertension

Cardiovascular risk correlates more closely with the systolic and thepulse pressure than with the diastolic pressure. In diabetic patients,the cardiovascular risk profile of diabetic patients is stronglycorrelated to duration of diabetes, glycemic control and blood pressure.Structural matrix proteins contribute to the function of vessels and theheart, and changes in the physical behavior of cardiovascular walls arebelieved to be important determinants of circulatory function. Inelderly individuals, the loss of compliance in the aorta leads toisolated systolic hypertension, which in turn expands the arterial walland thereby diminishes the dynamic range of elasticity. In vivo studiesin rodents, canines and in primates indicate potential utility of3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt in substantiallyameliorating vascular stiffening. For example, in a dog model fordiabetes, lower end diastolic pressure and increased end diastolicvolume, indicators of ventricular elasticity, returned to a value atabout the mid-point between the disease impaired value and the value forcontrol dogs. Treatment with3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt lead to a reductionin the mass of collagen in cardiovascular tissues. In situ hybridizationstudies demonstrate that 3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazoliumsalt reduces the expression of both Type IV collagen and TGFbeta.

Compared with that of a non-diabetic, the diabetic artery is smaller asit is stiffer. As in isolated systolic hypertension in which vesselsstiffen with age and lose the dynamic range of expansion under systole.First agents are used to treat, prevent, reduce or amelioratehypertension, including isolated systolic hypertension and diabetichypertension. Moreover, the same benefit is anticipated for the morerare hypertensive disorder, pulmonary hypertension. Pulmonaryhypertension is a rare blood vessel disorder of the lung in which thepressure in the pulmonary artery (the blood vessel that leads from theheart to the lungs) rises above normal levels and may become lifethreatening. The similarity in development of elevated blood pressure inthe pulmonary bed with the increase in systemic blood pressure indiabetic hypertension and in isolated systolic hypertension suggestssimilar mechanisms are involved.

Pulse pressure is the difference between systolic and diastolic bloodpressure. In a young human, systolic pressure is typically 120 mm Hg anddiastolic pressure is 80 mm Hg, resulting in a pulse pressure of 40 mmHg. With age, in many individuals pulse pressure increases, largely dueto the increase in systolic pressure that results from stiff vesseldisease. In individuals with pulse pressure greater than 60 mm Hg thereis an increased risk of death from cardiovascular morbidities. In aPhase IIa trial, one compound believed to work by a mechanism shared bythe compounds of the invention,3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt, reduced pulsepressure in elderly patients with pulse pressures greater than 60 mm Hgin a statistically significant manner. This decrease in pulse pressurewas believed to be due primarily to the effect of the agent on loweringthe systolic blood pressure.

The agents of the invention are used to treat, prevent, reduce orameliorate reduced vascular compliance, elevated pulse pressure, andhypertension. Moreover, the agents are used to reduce pulse pressure,increase vascular compliance, or decrease the risk of death.

Heart Failure

Congestive Heart Failure (CHF) is a clinical syndrome that entailscardiac disease of the ventricle. Diastolic dysfunction is a subset ofheart failure in which the left ventricle stiffens with age. Thestiffening of the left ventricle that occurs in CHF and in diastolicdysfunction is believed to result from increased crosslinking ofcollagen fibers with age and/or fibrosis and related hypertrophy. Firstagents are used to treat, prevent, reduce or ameliorate heart failure.

Retinopathy

The effect of diabetes on the eye is called diabetic retinopathy andinvolves changes to the circulatory system of the retina. The earliestphase of the disease is known as background diabetic retinopathy whereinthe arteries in the retina become weakened and leak, forming small,dot-like hemorrhages. These leaking vessels often lead to swelling oredema in the retina and decreased vision. The next stage isproliferative diabetic retinopathy, in which circulation problems causeareas of the retina to become oxygen-deprived or ischemic. New vesselsdevelop as the circulatory system attempts to maintain adequate oxygenlevels within the retina. Unfortunately, these new vessels hemorrhageeasily. In the later phases of the disease, continued abnormal vesselgrowth and scar tissue may cause serious problems such as retinaldetachment. First agents are used to treat, prevent, reduce orameliorate diabetic retinopathy. The first agents can be administered bythe methods described below, including by topical administration to theeye. The agents can also be administered by intravitreal implant.

Cataracts, Other Damage to Lens Proteins

AGE-mediated crosslinking and/or fibrotic processes are believed tocontribute to cataract formation and formation of other damage to lensproteins. First agents are used to treat, prevent, reduce or amelioratecataracts or other damage to lens proteins.

Alzheimer's Disease

Considerable evidence exists implicating AGEs that form in theneurofibrillary tangles (tau protein) and senile plaques (beta-amyloidpeptide) in early neurotoxic processes of Alzheimer's disease. Insolublehuman tau protein is likely crosslinked. Glycation of insoluble tau fromAD patients and experimentally AGE-modified tau generate oxygen freeradicals, resulting in the activation of transcription via nuclearfactor-kappa B, and resulting in an increase in amyloid beta-proteinprecursor and release of amyloid beta-peptides. Thus, A.G.E.-modifiedtau may function as an initiator in a positive feedback loop involvingoxidative stress and cytokine gene expression. First agents are used totreat, prevent, reduce or ameliorate Alzheimer's disease.

Other Indications

For reasons analogous to those set forth above, the invention isbelieved to be useful in treating, preventing, reducing or amelioratingdiabetes or its associated adverse sequelae, and peripheral neuropathy.The agents, especially in topical form, increase elasticity and/orreduce wrinkles in skin. The agents further increase red blood celldeformability.

Combination Therapies

In cardiovascular therapies, first agents can be administeredconcurrently or in a combined formulation with one or more antioxidants.Examples of appropriate antioxidants are vitamin A, vitamin B6, vitaminC, vitamin E, glutathione, β-carotene, α-lipoic acid, coenzyme Q10,selenium and zinc, which are administered in effective amounts as isknown in the art. Thus, the invention further provides pharmaceuticalcompositions comprising an agent of the invention in combination with aneffective amount of an antioxidant.

In treating heart failure, cardiomyopathy or heart attack, first agentscan be administered concurrently or in a combined formulation with oneor more angiotensin converting enzyme (ACE) inhibitors, angiotensin IIreceptor antagonists, calcium channel blockers, diuretics, digitalis orbeta blockers. Examples of ACE inhibitors include Captopril, Enalapril,Enalaprilat, Quinapril, Lisinopril and Ramipril, which are administeredin effective amounts as is known in the art. Examples of angiotensin IIreceptor antagonists include Losartan, Irbesartan, Eprosartan, Valsartanand Candesartan, which are administered in effective amounts as is knownin the art. Examples of calcium channel blockers include Amlopdipine,Bepridil, Diltiazem, Felodipine, Isradipine, Nicardipine, Nifedipine,Nimodipine and Verapamil, which are administered in effective amounts asis known in the art. Among diuretics, preferred examples includeFurosemide, Bumetanide, Torsemide, Ethacrynic acid, Azosemide,Muzolimine, Piretanide, Tripamide and Hydrochlorothiazide, which areadministered in effective amounts as is known in the art. Examples ofbeta adrenergic antagonists include Metoprolol, Carvedilol, Bucindolol,Atenolol, Esmolol, Acebutolol, Propranolol, Nadolol, Timolol, Pindolol,Labetalol, Bopindolol, Carteolol, Penbutolol, Medroxalol, Levobunolol,Bisoprolol, Nebivolol, Celiprolol and Sotalol, which are administered ineffective amounts as is known in the art. Thus, the invention furtherprovides pharmaceutical compositions comprising an agent of theinvention in combination with an effective amount of an ACE inhibitor,diuretic, digitalis, beta blocker, or combination thereof.

For treating diabetes or complications thereof, the invention furtherprovides pharmaceutical compositions comprising an agent of theinvention in combination with an effective amount of a thiazolidinedioneor “glitazone” diabetes drug, such as Troglitazone, Rosiglitazone, andPioglitazone.

In treating atherosclerosis, first agents can be administeredconcurrently or in a combined formulation with one or more statins (HMGCoA reductase inhibitors) or cholestyramine. Examples of statins includeMevastatin, Lovastatin, Simvastatin, Pravastatin and Fluvastatin, whichare administered in effective amounts as is known in the art. Thus, theinvention further provides pharmaceutical compositions comprising anagent of the invention in combination with an effective amount of astatin, cholestyramine, or both.

For a number of indications discussed, including sickle cell enemia anddiabetic complications, as well as wound healing and any otherindication in which increased tissue perfusion is a useful means oradjunct to therapy, the first agents, or aminoguanidine or other agentsof the aminoguanidine class can be administered with erythropoietin,which is administered in effective amount as is known in the art.Erythropoietin includes stable forms of erythropoietin such as aremarketed by Amgen (Thousand Oaks, Calif.).

For all indications, first agents can be administered concurrently or ina combined formulation with aminoguanidine or other agents of theaminoguanidine class, which are administered in effective amounts as isknown in the art.

The method of the invention is used to treat animals, preferablymammals, preferably humans.

In accordance with the present invention, methods for administeringpharmaceutical compositions containing certain compounds have beendeveloped for treating the indications described. These agents areeither substituted thiazolium, oxazolium, or imidazolium agents as shownin the Summary section above.

Pharmaceutical compositions of the invention include administering aneffective amount of a compound of the formula I.

The alkyl, and alkenyl groups referred to below include both C1 to C6linear and branched alkyl and alkenyl groups, unless otherwise noted.Alkoxy groups include linear or branched C1 to C6 alkoxy groups, unlessotherwise noted.

“Ar” (consistent with the rules governing aromaticity) refers to a C₆ orC₁₀ aryl, or a 5 or 6 membered heteroaryl ring. The heteroaryl ringcontains at least one and up to three atoms of N for the 6 memberedheteroaryl ring. The 5 membered heteroaryl ring contains; (1) from oneto three atoms of N, or (2) one atom of O or S and zero to two atoms ofN. The aryl or heteroaryl is optionally substituted as set forth below.Nonlimiting examples of heteroaryl groups include: pyrrolyl, furanyl,thienyl, pyridyl, oxazolyl, pyrazolyl, pyrimidinyl, and pyridazinyl.

“Ar” can be fused to either a benzene, pyridine, pyrimidine, pyridazine,or (1,2,3) triazine ring.

“Rs” refers to a C₆ or C₁₀ aryl group (optionally substituted as setforth below) or a heterocycle containing 4-10 ring members and 1-3heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur (wherein said heterocycle is optionally substituted as set forthbelow). Where Rs is a non aromatic heterocycle containing sulfur atom asring members, the sulfur atoms can exist in various oxidation states, asS(O)_(n), where n is 0, 1, or 2.

As used herein, C₆ or C₁₀ aryl groups and heterocycles containing 4 to10 ring members are monocyclic or bicyclic. The ring fusions of thebicyclic heterocycles are at carbon-carbon bonds.

In certain embodiments of the invention, the thiazoliums, imidazoliums,and oxazoliums of the invention contain R¹ and R² substitutions thattogether with their ring carbons (the C4-C5 carbons of the thiazoliums,imidazoliums, and oxazoliums) form a fused C5 to C7 cycloalkyl ringhaving up to two double bonds including the fused double bond (the C4-C5double bond of the thiazoliums, imidazoliums, and oxazoliums). Thecycloalkyl ring can be substituted by one or more of the groupconsisting of alkyl, alkoxycarbonyl, amino, aminocarbonyl, carboxy,fluoro, and oxo substituents. One of ordinary skill in the art willrecognized that where cycloalkyl groups contain double bonds, the sp²hybridized carbon atoms can contain only one substituent (which can notbe amino- or oxo-). Sp³ hybridized carbon atoms in the cycloalkyl ringcan be geminally substituted with the exception that (1) two aminogroups and (2) one amino and one fluoro group can not be substituted onthe same sp³ hybridized carbon atom.

In certain embodiments of the invention, the thiazoliums, imidazoliums,and oxazoliums of the invention contain R¹ and R² substitutions thattogether with their ring carbons (the C4-C5 carbons of the thiazoliums,imidazoliums, and oxazoliums) form a five to eight membered heterocycle(i.e. a bicyclic heterocycle is formed). In these embodiments theheterocycle is preferably not aromatic. Particular compounds withinthese embodiments contain sulfur atoms in the ring fused to thethiazoliums, imidazoliums, and oxazoliums. These sulfur atoms in theseparticular compounds can exist in various oxidation states, as S(O)_(n),where n is 0, 1, or 2.

In certain embodiments of the invention, the thiazoliums, imidazoliums,and oxazoliums of the invention contain R¹ and R² substitutions thattogether with their ring carbons (the C4-C5 carbons of the thiazoliums,imidazoliums, and oxazoliums) form a five or six membered heteroarylring (i.e, a bicyclic aromatic heterocycle is formed). A preferredbicyclic aromatic heterocycle of the invention is a purine analog [Q isN and R¹ and R² together with their ring carbons (the C4 and C5 of theimidazolium ring) form a pyrimidine ring].

In certain embodiments, the thiazoliums, imidazoliums, and oxazoliums ofthe invention contain a Y group which can be —CH(R⁵)—R⁶. In thoseembodiments where R⁵ is alkenyl, preferably alkenyl is —C═C—R^(E), whereR^(E) is alkyl, H, or hydroxy(C₁-C₆)alkyl. In those embodiments whereinR⁵ is alkynyl, preferably alkynyl is —C≡C—R^(F), where R^(F) is alkyl,hydrogen, or hydroxy(C₁-C₆)alkyl.

Aryl or Ar, can generally be substituted with, in addition to anysubstitutions specifically noted one or more substituents selected fromthe group consisting of acylamino, acyloxyalkyl, alkanoyl,alkanoylalkyl, alkenyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl,alkyl, alkylamino, (C₁-C₃)alkylenedioxy, alkylsulfonyl [alkylS(O)₂—],alkylsulfinyl [alkylS(O)—], ω-alkylenesulfonic acid [-alkylSO₃H wheren=1-6)], alkylthio, allyl, amino, ArC(O)—, ArO—, Ar—, Ar-alkyl-,carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl,hydroxy, (C₂-C₆)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid[—SO₃H], 1-pyrrolidinyl-, 4-[C6 or C10]arylpiperazin-1-yl-, 4-[C6 orC10]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl, andpiperidin-1-yl.

Heterocycles, except those of Ar, can generally be substituted withacylamino, alkanoyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylamino, alkylsulfonyl [alkylS(O)₂—], alkylsulfinyl [alkylS(O)—],alkylthio, amino, ArC(O)—, ArO—, Ar—, carboxy, dialkylamino, fluoro,fluoroalkyl, difluoroalkyl, hydroxy, mercapto, sulfamoyl, ortrifluoromethyl. Preferably multiple substituents are located ondifferent atoms of the heterocyclic ring, with the proviso that alkyl,alkylcarbonyl, and fluoro substituents can be substituted on the samecarbon atom of the heterocyclic ring. Heterocycles can be substitutedwith one or more substituents.

The halo atoms can be fluoro, chloro, bromo or iodo. Chloro and fluoroare preferred for aryl substitutions.

For the purposes of this invention, the compounds of formula (I) areformed as biologically or pharmaceutically acceptable salts. Useful saltforms include the halides (particularly bromides and chlorides),tosylates, methanesulfonates, brosylates, fumarates, maleates,succinates, acetates, mesitylenesulfonates, and the like. Other relatedsalts can be formed using similarly non-toxic, and biologically orpharmaceutically acceptable anions.

Representative, non-limiting examples of compounds of the presentinvention are:

-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]thiazolium bromide-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide-   3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(6-hydroxyhexyl)thiazolium    bromide-   3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-(2-(2-furanyl)-2-oxoethyl)-4-(2-hydroxypentyl)thiazolium bromide-   3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide-   3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-(2-hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethylthiazolium    bromide-   3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethylthiazolium    bromide-   3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethyl-thiazolium bromide-   3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-octylthiazolium bromide-   3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dioctadecylthiazolium bromide-   3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dipentylthiazolium    bromide-   3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-didodecylthiazolium bromide-   3-(2-(2-furanyl)-2-oxoethyl)-5-decylthiazolium bromide-   3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dioctylthiazolium    bromide-   3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-diethylthiazolium bromide-   3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dipentylthiazolium    bromide-   3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]thiazolium bromide-   3-(2-(2-thienyl)-2-oxoethyl)thiazolium bromide-   3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-(6-hydroxyhexyl)thiazolium    bromide-   3-(2-(4-thiomorpholinyl)-2-oxoethyl)thiazolium bromide-   3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dioctylthiazolium    bromide-   3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-didecylthiazolium    bromide-   3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dioctylthiazolium bromide-   3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dipropylthiazolium    chloride-   3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4-methylthiazolium    chloride-   3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-5-methylthiazolium    chloride-   3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4-octylthiazolium chloride-   3-aminothiazolium mesitylenesulfonate;-   3-amino-4,5-dimethylaminothiazolium mesitylenesulfonate;-   2,3-diaminothiazolinium mesitylenesulfonate;-   3-(2-methoxy-2-oxoethyl)thiazolium bromide;-   3-(2-methoxy-2-oxoethyl)-4,5-dimethylthiazolium bromide;-   3-(2-methoxy-2-oxoethyl)-4-methylthiazolium bromide;-   3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide;-   3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide;-   3-amino-4-methylthiazolium mesitylenesulfonate;-   3-(2-methoxy-2-oxoethyl)-5-methylthiazolium bromide;-   3-(3-(2-phenyl-2-oxoethyl)-5-methylthiazolium bromide;-   3-[2-(4-bromophenyl)-2-oxoethyl]thiazolium bromide;-   3-[2-(4-bromophenyl)-2-oxoethyl]-4-methylthiazolium bromide;-   3-[2-(4-bromophenyl)-2-oxoethyl]-5-methylthiazolium bromide;-   3-[2-(4-bromophenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-(2-phenyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-(4-bromophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3,4-dimethyl-5-(2-hydroxyethyl)thiazolium iodide;-   3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide;-   3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride;-   3-(2-methoxy-2-oxoethyl)benzothiazolium bromide;-   3-(2-phenyl-2-oxoethyl)benzothiazolium bromide;-   3-[2-(4′-bromophenyl)-2-oxoethyl]benzothiazolium bromide;-   3-(carboxymethyl)benzothiazolium bromide;-   2,3-(diamino)benzothiazolium mesitylenesulfonate;-   3-(2-amino-2-oxoethyl)thiazolium bromide;-   3-(2-amino-2-oxoethyl)-4-methylthiazolium bromide;-   3-(2-amino-2-oxoethyl)-5-methylthiazolium bromide;-   3-(2-amino-2-oxoethyl)-4,5-dimethylthiazolium bromide;-   3-(2-amino-2-oxoethyl)benzothiazolium bromide;-   3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-amino-5-(2-hydroxyethyl)-4-methylthiazolium mesitylenesulfonate;-   3-(2-methyl-2-oxoethyl)thiazolium chloride;-   3-amino-4-methyl-5-(2-acetoxyethyl)thiazolium mesitylenesulfonate;-   3-(2-phenyl-2-oxoethyl)thiazolium bromide;-   3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl)thiazolium    bromide;-   3-(2-amino-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl)thiazolium    bromide;-   2-amino-3-(2-methoxy-2-oxoethyl)thiazolium bromide;-   2-amino-3-(2-methoxy-2-oxoethyl)benzothiazolium bromide;-   2-amino-3-(2-amino-2-oxoethyl)thiazolium bromide;-   2-amino-3-(2-amino-2-oxoethyl)benzothiazolium bromide;-   3-[2-(4-methoxyphenyl)-2-oxoethyl]thiazolium bromide;-   3-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]thiazolium bromide;-   3-[2-(4-fluorophenyl)-2-oxoethyl]thiazolium bromide;-   3-[2-(2,4-difluorophenyl)-2-oxoethyl]thiazolium bromide;-   3-[2-(4-diethylaminophenyl)-2-oxoethyl]thiazolium bromide;-   3-propargylthiazolium bromide;-   3-propargyl-4-methylthiazolium bromide;-   3-propargyl-5-methylthiazolium bromide;-   3-propargyl-4,5-dimethylthiazolium bromide;-   3-propargyl-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide;-   3-(2-[3-methoxyphenyl]-2-oxoethyl)thiazolium bromide;-   3-(2-[3-methoxyphenyl]-2-oxoethyl)-4    methyl-5-(2-hydroxyethyl)thiazolium bromide;-   3-(2-[3-methoxyphenyl)-2-oxoethyl)-benzothiazolium bromide;-   2,3-diamino-4-chlorobenzothiazolium mesitylenesulfonate;-   2,3-diamino-4-methylthiazolium mesitylenesulfonate;-   3-amino-4-methyl-5-vinylthiazolium mesitylenesulfonate;-   2,3-diamino-6-chlorobenzothiazolium-   2,6-diamino-benzothiazole dihydrochloride;-   2,6-diamino-3-[2-(4-methoxyphenyl)-2-oxoethyl]benzothiazolium    bromide;-   2,6-diamino-3-[2-(3-methoxyphenyl)-2-oxoethyl]benzothiazolium    bromide;-   2,6-diamino-3-[2-(4-diethylaminophenyl)-2-oxoethyl]benzothiazolium    bromide;-   2,6-diamino-3-[2-(4-bromophenyl)-2-oxoethyl]benzothiazolium bromide;-   2,6-diamino-3-[2-(2-phenyl)-2-oxoethyl]benzothiazolium bromide;-   2,6-diamino-3-[2-(4-fluorophenyl-2-oxoethyl]benzothiazolium bromide;-   3-acetamido-4-methyl-5-thiazolyl-ethyl acetate mesitylenesulfonate;-   2,3-diamino-5-methylthiazolium mesitylenesulfonate;-   3-[2-(2-naphthyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-thiazolium    bromide;-   3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-(2,6-dichlorophenethylamino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-dibutylamino-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-(4-carbethoxyanilino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-(2-(2,6-diisopropylanilino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-amino-4-methyl-5-[2-(2,6-dichlorobenzyloxy)ethyl]thiazolium    mesitylenesulfonate;-   3-[2-(4-carbomethoxy-3-hydroxyanilino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   2,3-diamino-4,5-dimethylthiazolium mesitylene sulfonate;-   2,3-diamino-4-methyl-5-(2-hydroxyethyl)thiazolium mesitylene    sulfonate;-   2,3-diamino-5-(3,4-trimethylenedioxy phenyl)-thiazolium mesitylene    sulfonate;-   3-[2-(1,4-benzodioxan-6-yl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-(3,4-trimethylenedioxyphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-(2-[3,4-benzodioxan-6-yl]-2-oxoethyl)thiazolium bromide;-   3-[2-(3,4-trimethylenedioxyphenyl)-2-oxoethyl]thiazolium bromide;-   3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]thiazolium    bromide;-   3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-4-methylthiazolium    bromide;-   3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-5-methylthiazolium    bromide;-   3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-benzothiazolium    bromide;-   1-methyl-3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]imidazolium    bromide;-   3-[2-(4-n-pentylphenyl)-2-oxoethyl]thiazolium bromide;-   3-[2-(4-n-pentylphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-(4-diethylaminophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-(2-phenyl-2-oxoethyl)-4-methyl-5-vinylthiazolium bromide;-   3-[2-(3,5-tert-butyl-4-hydroxyphenyl)-2-oxoethyl)-4-methyl-5-vinylthiazolium    bromide;-   3-(2-tert-butyl-2-oxoethyl)thiazolium bromide-   3-(2-tert-butyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-(3′-methoxybenzyl)-4-methyl-5-(2-hydroxyethyl)thiazolium chloride;-   3-(2,6-dichlorobenzyl)-4-methyl-5-(2-hydroxyethyl)thiazolium    chloride;-   3-(2-nitrobenzyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;-   3[2-(4-chlorophenyl)-2-oxoethyl]thiazolium bromide;

3[2-(4-chlorophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazoliumbromide

-   3[2-(4-methoxyphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide.-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]thiazolium bromide-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide-   3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-methyl-5-(6-hydroxyhexyl)thiazolium    bromide-   3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-(2-(2-furanyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-(2-(2-furanyl)-2-oxoethyl)-4-(2-hydroxypentyl)thiazolium bromide-   3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide-   3-(2-(2-thienyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-hydroxyethylthiazolium    bromide-   3-(2-(4-thiomorpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dimethylthiazolium    bromide-   3-[2-(4-[2-methoxyphenyl]-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-dimethylthiazolium    bromide-   3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride-   3-[2-(3-phenyl-5-isoxazolyl)-2-oxoethyl]-4-octylthiazolium bromide-   3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dimethylthiazolium bromide-   3-[2-[4-(2-ethoxy-2-oxoethyl)-2-thiazolyl]amino-2-oxoethyl]-4,5-dipropylthiazolium    chloride-   3-(2-(4-morpholinyl)-2-oxoethyl)-4,5-dioctadecylthiazolium bromide-   3-[2-(2,6-dimethyl-4-morpholinyl)-2-oxoethyl]-4,5-dipentylthiazolium    bromide-   3-(2-(1-piperidinyl)-2-oxoethyl)-4,5-didodecylthiazolium bromide-   3-(2-(2-furanyl)-2-oxoethyl)-5-decylthiazolium bromide-   3-[2-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-oxoethyl]-4,5-dioctylthiazolium    bromide-   3-(2-(1-pyrrolidinyl)-2-oxoethyl)-4,5-diethylthiazolium bromide-   3-[2-(3-methyl-2-thianaphthenyl)-2-oxoethyl]-4,5-dipentylthiazolium    bromide-   3-[2-(4-phenyl-1-piperazinyl)-2-oxoethyl]thiazolium bromide-   3-(2-(2-thienyl)-2-oxoethyl)thiazolium bromide-   3-(2-(2-thienyl)-2-oxoethyl)-4-methyl-5-(6-hydroxyhexyl)thiazolium    bromide-   3-(2-(4-thiomorpholinyl)-2-oxoethyl)thiazolium bromide-   3-(2-(hexahydro-1-azepinyl)-2-oxoethyl)-4,5-dioctylthiazolium    bromide-   3-(2-(octahydro-1-azocinyl)-2-oxoethyl)-4,5-didecylthiazolium    bromide-   3-(2-(2-pyridinyl)-2-oxoethyl)-4,5-dioctylthiazolium bromide-   3-[2-(2-methyl-1-piperidinyl)-2-oxoethyl]-4,5-dipropylthiazolium    chloride-   3-[2-(2,6-dimethyl-1-piperidinyl)-2-oxoethyl]-4-methylthiazolium    chloride-   3-[2-(4-benzyl-1-piperidinyl)-2-oxoethyl]-5-methylthiazolium    chloride-   3-[2-(4-benzyl-1-piperazinyl)-2-oxoethyl]-4-octylthiazolium chloride-   1-methyl-3-[2-(3-methoxyphenyl)-2-oxoethyl]imidazolium bromide;-   1-methyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]imidazolium bromide;-   1-methyl-3-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]imidazolium bromide;-   1-methyl-3-[2-(4-diethylaminophenyl)-2-oxoethyl]imidazolium bromide;-   1-methyl-3-[2-amino-2-oxoethyl]imidazolium bromide;-   1-methyl-2-amino-imidazolium mesitylene sulfonate;-   1-methyl-3-[2-phenyl-2-oxoethyl]imidazolium bromide;-   3-amino-1-(ethoxycarbonylpentyl)imidazolium mesitylenesulfonate;-   1-(ethoxycarbonylpentyl)-3-[2-(3-methoxyphenyl)-2-oxoethyl]imidazolium    bromide;-   1-methyl-3-[2-(4-bromophenyl)-2-oxoethyl]imidazolium bromide;-   1-methyl-3-[2-(4-fluorophenyl)-2-oxoethyl]imidazolium bromide;-   1-methyl-3-[2-(3,4-difluorophenyl)-2-oxoethyl]imidazolium bromide;-   1-(ethoxycarbonylpentyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]imidazolium    bromide;-   1-(4-acetylphenyl)-3-amino-imidazolium mesitylenesulfonate;-   1-(ethoxycarbonylpentyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]imidazolium    bromide;-   1-(ethoxycarbonylpentyl)-3-[2-(4-methylphenyl)-2-oxoethyl]imidazolium    bromide;-   1-amino-3-benzoyl-imidazolium mesitylene sulfonate;-   1-methyl-3-(2-naphth-2-yl-2-oxoethyl)imidazolium bromide;-   1-methyl-3-[(4-biphen-1-yl)-2-oxoethyl]imidazolium bromide;-   1-methyl-3-[(3-trifluoromethylphenyl)-2-oxoethyl)]imidazolium    bromide;-   1-methyl-3-[4-(2,4-difluorophenyl)-2-oxoethyl]imidazolium chloride;-   3-[2-(thien-2-yl)-2-oxoethyl]-1-methyl-5-imidazolium bromide;-   1-methyl-3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]imidazolium    bromide;-   1-methyl-3-[2-(2,4-dichlorophenyl)-2-oxoethyl]imidazolium chloride;-   3-(2-phenyl-2-oxoethyl)-1-phenylimidazolium chloride;-   3-(2-phenyl-2-oxoethyl)-1-ethylimidazolium chloride;-   3-(2-phenyl-2-oxoethyl)-1-butylimidazolium chloride;-   3-(2-phenyl-2-oxoethyl)-1-allylimidazolium chloride;-   3-(2-trifluoromethylphenyl-2-oxoethyl)-4,5-dimethylthiazolium    bromide;-   3-(2-trifluoromethylphenyl-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-(2-trifluoromethylphenyl-2-oxoethyl)-1-methylimidazolium bromide;-   3-(2-trifluoromethylphenyl-2-oxoethyl)-1-methylimidazolium bromide;-   1-butyl-3-amino-imidazolium-mesitylenesulfonate;-   3-[2-(thien-2-yl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-(2-phenyl-2-oxoethyl)-1,2-dimethylimidazolium chloride;-   3-amino-1,2-dimethylimidazolium mesitylenesulfonate;-   3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-1-ethylimidazolium chloride;-   3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-1-phenylimidazolium chloride;-   3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-1-methylimidazolium chloride;-   3-[2-(thien-2-yl)-2-oxoethyl]-1-ethylimidazolium bromide;-   3-[2-(thien-2-yl)-2-oxoethyl]-1-phenylimidazolium bromide;-   3-[2-(thien-2-yl-2-oxoethyl]-1,4,5-trimethylimidazolium bromide;-   3-[2-(pyrrolidin-2-yl)-2-oxoethyl]-1,4,5-trimethylimidazolium    chloride;-   3-[2-(4-chlorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(4-bromophenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(4-fluorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(2,4-difluorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(3,4-difluorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(2-methoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(3-methoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(4-methoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(2,4-dimethoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(2,5-dimethoxyphenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(4-methylphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(4-diethylaminophenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-amino-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxoethyl]-1,2-dimethyl-imidazolium    bromide;-   3-[2-(3,4-trimethylenedioxyphenyl)-2-oxoethyl]-1,2-dimethyl-imidazolium    bromide;-   3-[2-(4-biphenyl)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(3,5-dichloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(4-trifluoromethylphenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(2,6-dichlorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(thiomorpholin-4-yl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(morpholin-4-yl)-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-(piperidin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-hexamethyleneimino-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-heptamethyleneimino-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-naphthyl-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(2-trifluoromethylphenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(2-trifluoromethylphenyl)-2-oxoethyl]-2,4,5-trimethylthiazolium    bromide;-   3-(2-methyl-2-oxoethyl)-1,2-dimethylimidazolium chloride;-   3-(2-phenyl-2-oxoethyl)-2-amino-1-methylbenzimidazolium chloride;-   3-[2-(thiomorpholin-4-yl)-2-oxoethyl]-1-methylimidazolium chloride;-   3-[2-(4-phenylpiperazin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-{6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalyl)}-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(1,4-benzodioxan-6-yl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-(phenyl)-2-oxoethyl]-5-chloro-3-methyl-1-ethylimidazolium    chloride;-   3-[2-(phenyl)-2-oxoethyl]-4-methyl-2-ethylthiazolium chloride;-   3-(2-phenyl-2-oxoethyl)-1-methyl-2-aminoimidazolium chloride;-   3-[2-(pyrrolidin-2-yl)-2-oxoethyl]-2-amino-1-methylimidazolium    chloride;-   3-(2-phenyl-2-oxoethyl)-1,2-dimethyl-5-nitroimidazolium chloride;-   3-[2-(4-acetylanilino)-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-(4-carboethoxyanilino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2,6-diisopropylanilino)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-anilino-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[(4-bromoanilino)-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-(4-[morpholin-4-yl]phenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-dibutylamino-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-(2,6-dichloro-phenethylamino)-2-oxoethyl]-1,2-dimethylimidazolium;-   3-[2-(3-hydroxy-4-methoxycarbonylanilino)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   3-[2-cyclopentylamino-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-neopentylamino-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-(pyridin-2-yl)-2-oxoethyl]-4,5-dimethylimidazolium bromide;-   3-(2-phenyl-2-oxoethyl)-1,4,5-trimethylimidazolium chloride;-   3-(2-phenyl-2-oxoethyl)-1,2,4,5-tetramethylimidazolium chloride;-   3-[2-(6-[1,2,3,4-tetrahydroquinolinyl])-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2,6-difluorophenyl)-2-oxoethyl]-1,2-dimethylimidazolium    bromide;-   1-vinyl-3-[2-phenyl-2-oxoethyl]imidazolium chloride;-   1-(4-hydroxyphenyl)-3-(2-phenyl-oxoethyl)imidazolium chloride;-   1-(4-acetylphenyl)-3-(2-phenyl-2-oxoethyl)imidazolium chloride;-   1-methyl-3-(2-phenyl-2-oxoethyl)benzimidazolium chloride;-   1,5-dicyclohexyl-3-(2-phenyl-2-oxoethyl)imidazolium chloride;-   1-(4-methoxycarbonylphenyl)-3-(2-phenyl-2-oxoethyl)imidazolium    chloride;-   1-benzyl-3-(2-phenyl-2-oxoethyl)imidazolium chloride;-   1-(4-methoxyphenyl)-3-(2-phenyl-2-oxoethyl)imidazolium chloride;-   3-[2-(tert-butylamino)-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-(2,4-difluoroanilino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2,4,6-trimethylanilino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-(2-cyclohexylamino-2-oxoethyl)-1,2-dimethylimidazolium chloride;-   3-[2-(4-carboxy-3′-hydroxyanilino)-2-oxoethyl)-1,2-dimethylimidazolium    chloride;-   3-[2-([2-morpholin-4-yl]ethylamino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(3-[2-methylpiperidin-1-yl]propylamino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-(2-veratrylamino-2-oxoethyl)-1,2-dimethylimidazolium chloride;-   3-[2-(thiazolidin-3-yl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(1-adamantanamino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2-adamantanamino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2-indanylamino)-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-(2′-[3″-chlorobenzoyl]-5-chloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(4-ethoxycarbonylthiazol-2-yl)amino-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-(cyclohexylamino-2-oxoethyl)-2,4,5-trimethylthiazolium chloride;-   3-[2-(2-chloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium bromide;-   3-[2-(2-chloroanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium    bromide;-   3-[2-(3,4-dimethoxyphenethylamino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2,4-dichloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2,6-dichloroanilino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[(2-pyrrolidin-1-yl)-2-oxoethyl]-1,2,4,5-tetramethylimidazolium    chloride;-   3-[2-(4-[pyrrolidin-1-yl]piperidin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(4-[piperidin-1-yl]piperidin-1-yl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2,6-difluoroanilino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-(2-cyclobutylamino-2-oxoethyl)-1,2-dimethylimidazolium chloride;-   3-[2-(3,5-difluoroanilino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(2-fluoroanilino)-2-oxoethyl]-1,2-dimethylimidazolium chloride;-   3-[2-(1R,2R,3R,5S-isopinocampheylamino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(1,3,3-trimethyl-6-azabicyclo[3,2,1]octanyl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   3-[2-(1,2,3,4-tetrahydro-1-naphthylamino)-2-oxoethyl]-1,2-dimethylimidazolium    chloride;-   1-(4-methoxyphenyl)-3-aminoimidazolium mesitylenesulfonate;-   1-benzyl-3-aminoimidazolium mesitylenesulfonate;-   1-vinyl-3-aminoimidazolium mesitylenesulfonate;-   1-methyl-3-aminoimidazolium mesitylenesulfonate;-   1-(4-methoxycarbonylphenyl)-3-aminoimidazolium mesitylenesulfonate;-   3-(2-phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium;-   S(−) 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium chloride;-   R(−) 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium chloride;-   3-[2-(2-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(3-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(4-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-(2-phenyl-2-oxoethyl)-4-methyl-5-(hydroxymethyl)-thiazolium    chloride;-   3-[2-(2,4-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(3,5-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(2,5-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(3,4-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride;-   3-[2-(2′,3′-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium;-   thiamine hydrochloride;-   (1-ethyl-hexanoate)-3-[2-(4-chlorophenyl)-2-oxoethyl]imidazolium    bromide;-   3-[2-[6-[1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalyl]]-2-oxoethyl]thiazolium    bromide;-   3-[2-(3,5-dichloroanilino)-2-oxoethyl]thiazolium bromide;-   3-[2-(4-biphenyl)-2-oxoethyl]thiazolium bromide;-   Cocarboxylase (diphosphate ester of thiamine HCl);-   monophosphate ester of thiamine HCl;-   3-[2-(9H-fluoren-2-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-{6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalyl)}-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-{5-(3-phenylisoxazolyl)}-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(4-biphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(3,5-dichloroanilino)-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-{6-[1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-naphthalyl]}-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-(3-phenylisoxazol-5-yl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-(4-biphenyl)-2-oxoethyl]-4-methyl-5-(2′-hydroxyethyl)thiazolium    bromide;-   3-[2-(3,5-dichloroanilino)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-{[2-(3-methoxybenzoyl)amino]benzyl}-4,5-dimethylthiazolium    bromide;-   3-[2-(2-amino-5-carboethoxymethylene-thiazolyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride;-   3-[2-(morpholin-4-yl-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(2,6-dimethylmorpholin-4-yl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(piperidin-1-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(fur-2-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-[6-(2-oxo-1,2,3,4-tetrahydroquinolinyl)]-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(pyrrolidin-1-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(4-carboxyanilino)-2-oxoethyl)-4,5-dimethylthiazolium chloride;-   3-[2-(2-{3-methylbenzo[b]thienyl})-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(4-phenylpiperazin-1-yl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(4-fluorophenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(4-methoxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(4-trifluoromethyl)-2-oxoethyl]-4,5-dimethyl-thiazolium    bromide;-   3-[2-(2,4-difluorophenyl)-2-oxoethyl]-4,5-dimethylthiazolium    bromide;-   3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride;-   3-[2-tert-butyl-2-oxoethyl]-4,5-dimethylthiazolium chloride;-   3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride;-   3-[2-(4-Diethylaminophenyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride;-   3-(2-methyl-2-oxoethyl)-4,5-dimethylthiazolium chloride;-   3-[2-(2,6-dichlorophenyl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride;-   3-(2-phenyl-2-oxoethyl)-4-phenylthiazolium chloride;-   3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4-phenylthiazolium chloride;-   3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4-phenylthiazolium bromide;-   3-(2-methyl-2-oxoethyl)-4-methyl-5-(hydroxyethyl) thiazolium    chloride;-   3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium;-   3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    chloride;-   3-(1-methyl-2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride;-   3-(phenylthiomethyl)-4,5-dimethylthiazolium chloride;-   3-[2-thien-2-yl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-(2-thien-2-yl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)thiazolium    bromide;-   3-[2-phenyl-2-oxoethyl]-4,5-cyclohexenyl-thiazolium bromide;-   3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4,5-cyclohexeno-thiazolium    chloride;-   3-(2-phenyl-2-oxoethyl)-4,5-cyclopenteno-thiazolium bromide;-   3-[2-(2,4-dichlorophenyl)-2-oxoethyl]-4,5-cyclopenteno-thiazolium    chloride;-   3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4,5-cyclopenteno-thiazolium    bromide;-   3-[2-(2,4,6-trimethylphenyl)-2-oxoethyl]-4,5-cyclopenteno-thiazolium    bromide;-   3-(2-cyanomethyl)-4,5-cyclohexeno-thiazolium bromide;-   3-(2-cyanomethyl)-4,5-cyclopenteno-thiazolium bromide;-   3-(2-cyanomethyl)-4,5-dimethyl-thiazolium bromide;-   3-(2-methyl-2-oxoethyl)-4,5-cyclopenteno-thiazolium chloride;-   3-(2-cyanomethyl)-4-methyl-5-(2-hydroxyethyl)thiazolium bromide;-   3-(2-phenyl-2-oxoethyl)-4-methyl-5-(hydroxyethylsuccinyl)thiazolium    chloride;-   3-[2-(thien-2-yl)-2-oxoethyl]-2,4,5-trimethylthiazolium bromide;-   3-amino-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide;-   3-(2-phenyl-2-oxoethyl)-2,4,5-trimethylthiazolium chloride;-   3-amino-2,4,5-trimethylthiazolium mesitylenesulfonate;-   3-[2-(4-{2-methoxyphenyl}piperazin-1-yl)-2-oxoethyl]-4,5-dimethylthiazolium    chloride;-   3-[2-hydroxy-2-oxoethyl]-4,5-dimethylthiazolium chloride;-   3-(2-phenyl-2-oxoethyl)-2-aminothiazolium chloride;-   3-[2-(thiomorpholin-4-yl)-2-oxoethyl]-5-hydroxyethyl-4-methylthiazolium    chloride;-   3-[2-(4-trifluoromethylphenyl)-2-oxoethyl]-2,4,5-trimethylthiazolium    bromide;-   3-[2-phenyl-2-oxoethyl]-2-isobutylthiazolium chloride;-   3-[2-(thiomorpholin-4-yl)-2-oxoethyl)-2,4,5-trimethylthiazolium    chloride;-   3-(2-amino-2-oxoethyl)-2-methylbenzothiazolium chloride;-   3-[2-(4-acetanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium chloride;-   3-[2-(4-carboethoxyanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium    bromide;-   3-[2-(2,6-diisopropylanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium    bromide;-   3-[(4-bromoanilino)-2-oxoethyl]-2,4,5-trimethylthiazolium chloride;-   3-[2-(2-naphthyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-([3-phenylisoxazol-5-yl])-2-oxoethyl]thiazolium bromide;-   3-methyl-4,5-dimethylthiazolium chloride;-   3-ethyl-4,5-dimethylthiazolium bromide;-   3-[2-(4′-acetoxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromide;-   3-[2-phenyl-2-oxoethyl]-4-methyl-5-(ethoxycarbonyl)thiazolium    chloride;-   3-[2-(4-diethylaminophenyl)-2-oxoethyl]thiazolium chloride;-   1-methyl-3-(2-cyanomethyl)imidazolium bromide;-   3-(2-cyanomethyl)-4,5-dimethylthiazolium bromide;-   3-(2-cyanomethyl)-4,5-cyclopentenothiazolium bromide;-   3-(2-cyanomethyl)-4,5-cyclohexenothiazolium bromide;-   1-methyl-3-(2-cyanomethyl)imidazolium bromide;-   1-vinyl-3-(2-cyanomethyl)imidazolium chloride;-   1-allyl-3-(2-cyanomethyl)imidazolium chloride;-   1-(4-acetylphenyl)-3-(2-cyanomethyl)imidazolium chloride;-   1-phenyl-3-(2-cyanomethyl)imidazolium chloride;-   1-(4-methoxyphenyl)-3-(2-cyanomethyl)imidazolium chloride;-   1-(4-methoxycarbonylphenyl)-3-(2-cyanomethyl-imidazolium chloride;-   3-(2-cyanomethyl)-1-methylbenzimidazolium chloride;-   1,5-dicyclohexyl-3-(2-cyanomethyl)imidazolium bromide;    as well as other biologically or pharmaceutically acceptable salts    thereof.

Compounds of the general formula I wherein the R¹, R², X, Y, and Z aredefined as above can be prepared by the methods of U.S. Pat. Nos.5,656,261; 5,853,703; and 6,007,865; or as described below. Moreover,certain of the compounds are conveniently prepared by chemical synthesesthat are well-known in the art. In addition, certain of the compoundsare well-known and readily available from chemical supply houses or canbe prepared by synthetic methods specifically published therefor. Thechemical reagents shown in the schemes below provide nonlimitingexamples of means well known in the art to carry out the reaction stepsshown.

Compounds of the invention wherein Y is CH(R⁵)—C(O)—R⁷ can be preparedaccording to the synthetic route depicted in Scheme 1 (wherein R¹, R²,R⁵, R⁷, M, Q, and Z are as described above, and X is a halide). Anacetyl derivative with a suitable a α leaving group, for example, anα-halo acetyl derivative, can be used to alkylate a suitably substitutedthiazole, oxazole, or imidazole. The alkylation reaction may beconducted at elevated temperatures in a suitable solvent, for example,acetonitrile or ethanol, or without solvent.

Compounds of the invention wherein R⁶ is a group of the formula—CH(OH)Rs may be prepared as shown in Schemes 2 and 3 (see below). Inthe nonlimiting exemplary synthetic schemes below, some productcompounds are shown as specific optical isomers and others are shown asracemic compounds. One skilled in the art will appreciate thatappropriate reaction conditions and reagents, that are well known in theart, can be used to customize the degree of reaction stereoselectivity.Thus, isolated stereoisomers are within the scope of compounds of theinvention. For example, compound 2 can be obtained as a racemic mixturefrom compound 1 or as an S (compound 2a) or R stereoisomer depending onthe reducing agent employed. Substitution of comparable reagents toachieve different stereoselectivity, even when not shown explicitly bythe scheme, is well known in the art at the time of filing. Moreover,synthetic processes and stereoselective purifications, such aschromatography on stereoselective media can be used to achieve 90%, 95%,98%, 99% or better isomeric purity, such that compositions substantiallyfree of the non-desired isomer can be prepared.

A synthetic scheme for making compounds of the formula I wherein Y isCH₂CH(OH)Rs is shown in Scheme 2. A hydroxyl is incorporated into anucleophile used to derivatize a thiazole compound, as follows:

where Lv is a leaving group such as chloro. In a related synthesis,Compound 1 is reduced with a stereoselective reducing agent such as (−)DIP-chloride [(−)-B-chlorodiisopinocampheylborane] or (+) DIP-chloride[(+)-B-chlorodiisopinocampheylborane]. For example:

Substitution of (+) DIP-chloride results predominately in the mirrorimage to compound 3a.

Scheme 4 exemplifies methods of preparing compounds of the formula Iwherein Y is a group of the formula —CH₂R⁶ wherein R⁶ is a substitutedor unsubstituted benzoyl moiety. In this particular preparation,acetophenones substituted in the phenyl moiety with hydroxy groups arederivatized to add a leaving group to the alpha methyl group, and theresulting intermediate is then used to alkylate thiazoles, asexemplified below:

In another synthesis, the preparation of compounds of the formula Iwherein R² is —CH₂OH are exemplified. Formamide is first converted tothioformamide by reaction with phosphorus pentasulfide. Thioformamide isreacted with ethyl 2-chloroacetoacetate in dry dioxane as follows:

Compound 8 can then be reacted with a suitable alkylating agent to makea compound of the invention.

Where R¹ is —CH₂OH and R² is —CH₃ in Formula I, the route shown inScheme 6 can be used. The preparation of a thiazole analog containing a4-hydroxymethyl group, for example, is shown below:

Compound 10 can then be alkylated with a suitable alkylating agent tomake a compound of the invention.

Note that reaction conditions indicated in the various reaction schemesare exemplary: such conditions as solvent and temperature are subject tomodification within ordinary skill.

A useful synthetic route for the preparation of compounds of formula Iwherein Y is —CH(R⁵)CN is shown in Scheme 7.

wherein M, Q, R¹, R², R⁵, Y and Z are as described in the text above,and X is a halide, mesitylenesulfonate or other biologically acceptableanion. In Scheme 7, the appropriately substituted imidazole, oxazole, orthiazole of formula 11 is contacted with a (e.g.) halo substitutedacetonitrile of formula 12 to produce compounds of the formula 13. Thereaction can be performed without any added solvent, or an anhydroussolvent can be utilized as the solvent medium. When a solvent is used,acetonitrile is a typical solvent for this reaction. Reaction times varyaccording to particular reactants and conditions, but are usually in therange of a few minutes to 48 hours at a temperature of 25-130° C.

Compounds of the formula 17 (below), wherein Y contains a carboxamidomoiety, can be synthesized according to method depicted in Scheme 8. Anappropriately substituted amine can be condensed with an activatedacetyl analog (for example, an acid chloride or acid anhydride),containing an additional leaving group alpha to the carbonyl group, toprovide the carboxamide 15. Compound 15 can then be used to alkylate theheterocycle 16 to yield a compound of the invention 17.

Other alkylation conditions can also be used. For example, thiazoles andimidazoles can be alkylated at the 1-position or the 2-position by vaporphase alkylation over an appropriate solid catalyst, using thecorresponding alcohol as the alkyl source. See, Ono et al., in Catalysisby Microporous Materials, Studies in Surface Science and Catalysis, Vol.94, Beyer et al., Eds., 1995, polypeptide. 697-704. Appropriatecatalysts include zeolite H—Y, zeolite H-ZSM-5 and H₃PW₁₂O₄₀ supportedon silica. Reaction conditions typically include high temperatures, suchas 260 and 300° C.

In addition, N-aryl substituted thiazoliums, oxazoliums and imidazoliumscan also be prepared. For example, fluoro phenyl compounds such as4-fluorobenzoic acid methyl ester can be used to substitute the N¹nitrogen of imidazole to make methyl-4-(1H-imidazol-1-yl)benzoate. See,Morgan et al., J. Med. Chem. 33: 1091-1097, 1990. These aryl substitutedimidazoliums can then be reacted with an alkylating agent, for example,an α-haloacetophenone analog, to prepare a compound of the invention.Also, the amine functions of imidazoles or amine-substituted thiazolescan be acylated by dehydration or other methods known in the art.

3-Aminothiazoliums, 3-aminooxazoliums, and 1-alkyl-3-aminoimidazoliumscan be prepared by reaction with O-mesitylene sulfonylhydroxylanine inmethylene chloride. The product mesitylenesulfonate salts can beconverted to their chloride salts through ion exchange with stronglybasic anion exchange resins.

Substituted oxazole intermediate that are suitable intermediates for thealkylation reactions, such as those shown in Schemes 1 and 7, can beprepared by methods known in the art. For instance, 2-unsubstitutedoxazoles can be formed by condensation of formamide with eitherα-hydroxy or α-haloketones intermediates (H. Bredereck, R. Gommpper, H.G. v. Shuh and G. Theilig, in Newer Methods of Preparative OrganicChemistry, Vol. III, ed. W. Foerst, Academic press, New York, 1964, p.241). The intermediates can cyclize under acid conditions to form theoxazole ring (Scheme 9). In addition, 2,4-disubstituted oxazoles can beprepared from α-haloketones and amides at higher temperatures using thesame method.

Oxazoles can be prepared by cyclization reactions of isonitriles (vanLeusen, A. M. Lect. Heterocycl. Chem. 1980, 5, S111; Walborsky, H. M.;Periasamy, M. P. in The Chemistry of Functional Groups, suppl. C, Patai,S., Rappoport, Z., Eds, Wiley-Interscience, 1983, p. 835; Hoppe, D.Angew. Chem. Int. Edn. Engl., 1974, 13, 789: Schollkopf, U. Angew. Chem.Int. Ed. Engl., 1977, 16, 339). For example, as shown below in Scheme10, the tosylmethyl isocyanide can be deprotonated by a base and reactedwith a suitable electrophile (e.g. an aldehyde). The intermediate cancyclize and aromatize to provide the desired oxazole intermediate. Theintermediate can then be N-alkylated by the above-described methods tofurnish a compound of the invention. Other methods for preparing oxazoleintermediates include 1,5-dipolar cyclization of acylated nitrile ylides(Taylor E. C.; Turchi, I. J. Chem. Rev., 1979, 79, 181: Huisgen, R.Angew. Chem. Int. Edn. Engl. 1980, 19, 947).

Benzoxazole intermediates substituted at the 2 position can be preparedfrom 2-aminophenols by acylation with, for example, with an acidchloride and cyclization (Scheme 11). The intermediate can then beN-alkylated by the above-described methods to furnish a compound of theinvention.

To treat the indications of the invention, an effective amount of apharmaceutical compound will be recognized by clinicians but includes anamount effective to treat, reduce, ameliorate, eliminate or prevent oneor more symptoms of the disease sought to be treated or the conditionsought to be avoided or treated, or to otherwise produce a clinicallyrecognizable change in the pathology of the disease or condition.

Pharmaceutical compositions can be prepared to allow a therapeuticallyeffective quantity of the compound of the present invention, and caninclude a pharmaceutically acceptable carrier, selected from knownmaterials utilized for this purpose. See, e.g., Remington, The Scienceand Practice of Pharmacy, 1995; Handbook of Pharmaceutical Excipients,3^(rd) Edition, 1999. Such compositions can be prepared in a variety offorms, depending on the method of administration, such as sublingual,rectal, nasal, vaginal, topical (including the use of a patch or othertransdermal delivery device), by pulmonary route by use of an aerosol,or parenteral, including, for example, intramuscular, subcutaneous,intraperitoneal, intraarterial, intravenous or intrathecal.

In addition to the subject compound, the compositions of this inventioncan contain a pharmaceutically-acceptable carrier. The term“pharmaceutically-acceptable carrier”, as used herein, means one or morecompatible solid or liquid filler diluents or encapsulating substancesthat are suitable for administration to an animal, including a mammal orhuman. The term “compatible”, as used herein, means that the componentsof the composition are capable of being comingled with the subjectcompound, and with each other, such that there is no interaction thatwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use. Preferably when liquid dose forms areused, the compounds of the invention are soluble in the components ofthe composition. Pharmaceutically-acceptable carriers should, of course,be of sufficiently high purity and sufficiently low toxicity to renderthem suitable for administration to the animal being treated.

Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starchand-potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe Tween™ brand emulsifiers; wetting agents, such sodium laurylsulfate; coloring agents; flavoring agents; tableting agents,stabilizers; antioxidants; preservatives; pyrogen-free water; isotonicsaline; and phosphate buffer solutions. The choice of apharmaceutically-acceptable carrier to be used in conjunction with thesubject compound is basically determined by the way the compound is tobe administered. If the subject compound is to be injected, thepreferred pharmaceutically-acceptable carrier is sterile, physiologicalsaline, with a blood-compatible suspending agent, the pH of which hasbeen adjusted to about 7.4.

If the preferred mode of administering the subject compound isperorally, the preferred unit dosage form is therefore tablets,capsules, lozenges, chewable tablets, and the like. Such unit dosageforms comprise a safe and effective amount of the subject compound,which is preferably from about 0.7 or 3.5 mg to about 280 mg/70 kg, morepreferably from about 0.5 or 10 mg to about 210 mg/70 kg. Thepharmaceutically-acceptable carrier suitable for the preparation of unitdosage forms for peroral administration are well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcrosscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder-mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical for the purposes of thisinvention, and can be readily made by a person skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Such liquid oral compositions preferably comprise from about 0.012% toabout 0.933% of the subject compound, more preferably from about 0.033%to about 0.7%. Typical components of carriers for syrups, elixirs,emulsions and suspensions include ethanol, glycerol, propylene glycol,polyethylene glycol, liquid sucrose, sorbitol and water. For asuspension, typical suspending agents include methyl cellulose, sodiumcarboxymethyl cellulose, cellulose (e.g. Avicel™, RC-591), tragacanthand sodium alginate; typical wetting agents include lecithin andpolyethylene oxide sorbitan (e.g. polysorbate 80). Typical preservativesinclude methyl paraben and sodium benzoate. Peroral liquid compositionsmay also contain one or more components such as sweeteners, flavoringagents and colorants disclosed above.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual and buccal dosage forms. Such compositionstypically comprise one or more of soluble filler substances such assucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions can also be used to deliver the compound to the site whereactivity is desired; such as eye drops, gels and creams for oculardisorders.

Compositions of this invention include solutions or emulsions,preferably aqueous solutions or emulsions comprising a safe andeffective amount of a subject compound intended for topical intranasaladministration. Such compositions preferably comprise from about 0.01%to about 10.0% w/v of a subject compound, more preferably from about0.1% to about 2.0%. Similar compositions are preferred for systemicdelivery of subject compounds by the intranasal route. Compositionsintended to deliver the compound systemically by intranasal dosingpreferably comprise similar amounts of a subject compound as aredetermined to be safe and effective by peroral or parenteraladministration. Such compositions used for intranasal dosing alsotypically include safe and effective amounts of preservatives, such asbenzalkonium chloride and thimerosal and the like; chelating agents,such as edetate sodium and others; buffers such as phosphate, citrateand acetate; tonicity agents such as sodium chloride, potassiumchloride, glycerin, mannitol and others; antioxidants such as ascorbicacid, acetylcystine, sodium metabisulfote and others; aromatic agents;viscosity adjustors, such as polymers, including cellulose andderivatives thereof; and polyvinyl alcohol and acids and bases to adjustthe pH of these aqueous compositions as needed. The compositions mayalso comprise local anesthetics or other actives. These compositions canbe used as sprays, mists, drops, and the like.

Other preferred compositions of this invention include aqueoussolutions, suspensions, and dry powders comprising a safe and effectiveamount of a subject compound intended for atomization and inhalationadministration. Such compositions are typically contained in a containerwith attached atomizing means. Such compositions also typically includepropellants such as chlorofluorocarbons 12/11 and 12/114, and moreenvironmentally friendly fluorocarbons, or other nontoxic volatiles;solvents such as water, glycerol and ethanol, including cosolvents asneeded to solvate or suspend the active agent; stabilizers such asascorbic acid, sodium metabisulfite; preservatives such ascetylpyridinium chloride and benzalkonium chloride; tonicity adjustorssuch as sodium chloride; buffers; and flavoring agents such as sodiumsaccharin. Such compositions are useful for treating respiratorydisorders, such as asthma and the like.

Other preferred compositions of this invention include aqueous solutionscomprising a safe and effective amount of a subject compound intendedfor topical ocular administration. Such compositions preferably comprisefrom about 0.01% to about 0.8% w/v of a subject compound, morepreferably from about 0.05% to about 0.3%. Such compositions alsotypically include one or more of preservatives, such as benzalkoniumchloride or thimerosal; vehicles, such as poloxamers, modifiedcelluloses, povidone and purified water; tonicity adjustors, such assodium chloride, mannitol and glycerin; buffers such as acetate,citrate, phosphate and borate; antioxidants such as sodiummetabisulfite, butylated hydroxy toluene and acetyl cysteine; acids andbases can be used to adjust the pH of these formulations as needed.

Other preferred compositions of this invention useful for peroraladministration include solids, such as tablets and capsules, andliquids, such as solutions, suspensions and emulsions (preferably insoft gelatin capsules), comprising a safe and effective amount of asubject compound. Such compositions can be coated by conventionalmethods, typically with pH or time-dependent coatings, such that thesubject compound is released in the gastrointestinal tract at varioustimes to extend the desired action. Such dosage forms typically include,but are not limited to, one or more of cellulose acetate phthalate,polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate,ethyl cellulose, Eudragit™ coatings, waxes and shellac.

The compounds of the invention are administered by ocular, oral,parenteral, including, for example, using formulations suitable as eyedrops. For ocular administration, ointments or droppable liquids may bedelivered by ocular delivery systems known to the art such asapplicators or eye droppers. Such compositions can include mucomimeticssuch as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, preservatives such as sorbic acid,EDTA or benzylchromium chloride, and the usual quantities of diluentsand/or carriers. See, Remington's Pharmaceutical Sciences, 16th Ed.,Mack Publishing, Easton, Pa., 1980, as well as later editions, forinformation on pharmaceutical compounding.

Numerous additional administration vehicles will be apparent to those ofordinary skill in the art, including without limitation slow releaseformulations, liposomal formulations and polymeric matrices.

In another preferred embodiment, the pharmaceutically effective amountis approximately 0.1 or 0.5 to 4 mg/kg body weight daily. Still morepreferably, the pharmaceutically effective amount is approximately 1mg/kg body weight daily. In a preferred embodiment, the amount isadministered in once daily doses, each dose being approximately 1 mg/kgbody weight.

The activity of the compounds of the invention in breaking, reversing orinhibiting the formation of AGE's or AGE-mediated crosslinks can beassayed by any of the methods described in U.S. Pat. No. 5,853,703.

The following examples further illustrate the present invention, but ofcourse, should not be construed as in any way limiting its scope.

EXAMPLE

Rats received a daily intraperitoneal dose of 10 mg/kg3-[2-phenyl-2-oxoethyl]-4,5-dimethyl-thiazolium salt (compound A) (n=14)or placebo (n=15) for 30 days. The animals then underwent a thoracotomyand the left anterior descending coronary artery ligated. The chest wasthen closed and the animals allowed to recover for 14 days whilecontinuing to be treated with compound A or placebo. The animals werethen sacrificed and the hearts removed for histological examination. Theweight of the infarcted tissue was 0.16±0.04 g for the placebo treatedanimals compared to 0.11±0.05 g for the compound A treated animals(p=0.04). The thickness of the ventricular wall in the infarcted zonewas also reduced in the compound A treated animals compared to placebo(2.72±0.13 mm vs. 2.56±0.22 mm, p=0.09).

Example 1 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium chloride:2-Chloro-1-phenylethanol

2-Chloroacetophenone (5.0 g, 32 mmol) was dissolved in methanol (25 mL)and cooled to 0° C. Sodium borohydride (1.2 g, 32 mmol) was added andstirred at 0° C. for 30 minutes. The reaction mixture was neutralized byadding conc. HCl to pH 7.0 and evaporated to dryness. The residue wasdissolved in ethanol (30 mL) and filtered, washed with ethanol. Theethanol was evaporated to dryness. The residue was dissolved inmethylene chloride (20 mL) and dried over sodium sulfate. The methylenechloride solution was filtered and evaporated to give the desiredproduct as an oil; yield 4.84 g (5.6%).

3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium Chloride

The neat mixture of 2-chloro-1-phenylethanol (2.34 g, 14.9 mmol) and4,5-dimethylthiazole (1.69 g, 14.9 mmol) were heated with stirring at135° C. for 28 hrs. It was cooled to room temperature and water (30 mL)was added to the reaction mixture with stirring, and then was extractedwith ether (30 mL). The water layer was treated with actived carbon andevaporated to dryness. It was crystallized from a mixture ofacetonitrile and ether to give a racemic product as prisms; 0.39 g(9.7%); mp. 201-203° C.

Example 2 S 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium ChlorideS(−) 2-chloro-1-phenylethanol

2-Chloroacetophenone (3 g., 19.4 mmol) was treated with (−) DIP-chloride(6.7 g., 20.9 mmol) in anhydrous THF (20 mL) at dry-ice bath temperatureand left overnight. The temperature was raised to room temperature andTHF was removed in vacuo. The residue was dissolved in ether (100 mL).The diethanolamine (4.58 g., 42.6 mmol) was added and the mixturestirred at room temperature for 5 hrs. The separated solid was filteredand the filtered cake was washed with hexane (40 mL) and ether (30 mL).The combined filtrates were evaporated to dryness to give 6.36 g ofcrude product. This was purified by silica gel column chromatographyusing 1% ether and petroleum ether 1.71 g (56%) of the desired productwas obtained as an oil.

S 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium Chloride

The neat mixture of S(−) 2-chloro-1-phenylethanol (2.78 g., 17.8 mmol)and 4,5-dimethylthiazole (2 g., 17.7 mmol) were heated with stirring at135° C. for 25 hrs. It was cooled to room temperature and water (30 mL)was added to the reaction mixture with stirring. The solution wasextracted with ether (30 mL). The ether extract was again extracted withwater (30 mL). The combined water layer was evaporated to dryness andthe residue was crystallized with a mixture of acetonitrile and methyltert-butyl ether. Yield: 0.63 g. (7.7%); mp. 189-190° C.; [α]_(D) ²⁵−51.765 (Water, c=1.7732).

Example 3 R(+) 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazoliumChloride R(+) 2-chloro-1-phenylethanol

2-Chloroacetophenone (6.25 g., 40.4 mmol) was treated with (+)DIP-chloride (18 g., 56.1 mmol) in anhydrous THF (40 mL) at dry-ice bathtemperature and left overnight. The temperature was raised to roomtemperature and THF was removed in vacuo. The residue was dissolved inether (210 mL). The diethanolamine (9 g., 8 5.6 mmol) was added and themixture stirred at room temperature for 5 hrs. The separated solid wasfiltered and the filtered cake was washed with ether (150 mL). Thecombined filtrates were evaporated to dryness to give 15.53 g. of crudeproduct. This was purified by silica gel column chromatography using 1%ether and petroleum ether 4.32 g. (68%) of the desired product as anoil.

R(+) 3-(2-Phenyl-2-hydroxyethyl)-4,5-dimethylthiazolium Chloride

The neat mixture of R(+) 2-chloro-1-phenylethanol (4.32 g., 27.6 mmol)and 4,5-dimethylthiazole (3.12 g, 27.6 mmol) were heated with stirringat 135° C. for 25 hrs. It was cooled to room temperature and water (30mL) was added to the reaction mixture with stirring. The solution wasextracted with ether (30 mL). The ether extract was again extracted withwater (30 mL). The combined water layer was evaporated to dryness andthe residue was crystallized with a mixture of acetonitrile and methyltert-butyl ether. Yield: 0.44 g. (5.4%); mp. 187-189° C.; [α]_(D)²⁵+52.009 (Water, c=1.7824).

Example 4 3-[2-(2′,3′ or4′-monohydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium Bromide2-Bromo-4′-hydroxyacetophenone

Copper (II) bromide (6 g, 26.9 mmol) was suspended in ethyl acetate (50mL) and 4′-hydroxyacetophenone (2 g, 14.7 mmol) dissolved in chloroform(20 mL) was added to the suspension. The reaction mixture was refluxedfor 8 hrs. and filtered hot through celite pad. The filtrate wasevaporated to dryness to give the desired crude brown colored compound(mp=115-118° C.; yield: 3.03 g, 96%). The NMR spectrum and TLC [silicagel, Hexanes:EtOAc (1:1, v/v)] was in agreement with the desiredproduct. It was used as such in the next step of the reaction withoutfurther purification.

This method was used to prepare:

(i) 2-Bromo-2′-hydroxyacetophenone from 2′-hydroxyacetophenone andcopper (II) bromide. Yield: 3.30 g. (95%; oil).(ii) 2-Bromo-3′-hydroxyacetophenone from 3′-hydroxyacetophenone andcopper (II) bromide. Yield: 3.20 g. (92%; oil).

3-[2-(4-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium Bromide

The neat mixture of 2-bromo-4′-hydroxyacetophenone (3 g, 15 mmol) and4,5-dimethylthiazole (1.71 g, 15 mmol) was heated at 110° C. for 3 hrs.It was dissolved in acetonitrile (15 mL) and cooled to room temperature.Tert-butyl methyl ether (5 mL) was added and the reaction mixture keptat room temperature overnight. The product crystallized was filtered,washed well with a mixture of acetonitrile and tert-butyl methyl ether(1:1, v/v) and dried. It was recrystallized from a mixture ofacetonitrile, ethyl alcohol and tert-butyl methyl ether. Yield: 3.18 g(64%); mp. 245-247° C. (dec.).

This method was used to prepare:

(i) 3-[2-(2-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromidefrom 2-bromo-2′-hydroxyacetophenone and 4,5-dimethylthiazole. Yield:2.05 g. (38%), mp=208-209° C.(ii) 3-[2-(3-Hydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium bromidefrom 2-bromo-3′-hydroxyacetophenone and 4,5-dimethylthiazole. Yield:1.52 g. (47%), mp=235-237° C.

Example 5 3-(2-Phenyl-2-oxoethyl)-4-methyl-5-(hydroxymethyl)thiazoliumChloride Thioformamide

To formamide (20 g, 443 mmol) dissolved in anhydrous THF (100 mL) wasadded phosphorous pentasulfide (P₂S₅) (20 g, 45 mmol) while maintainingthe temperature at 30-35° C. The mixture was stirred overnight at roomtemperature, filtered and stripped of THF. The crude product wassuspended in ethyl acetate (40 mL) and cooled at −78° C. overnight,filtered and dried in vacuo at room temperature to give thioformamide(10.6 g, 39%). See Rynbrandt, R. H., Nishizawa, E. E., Balogoyen, D. P.,Mezdoza, A. K., Annis, K. A.; J. Med. Chem. 1981, 24, 1507-1510.

4-Methyl-5-(ethoxycarbonyl)thiazole

Thioformamide (7.5 g, 122.72 mmol), ethyl 2-chloroacetoacetate (16.4 g,99.52 mmol) and magnesium carbonate (20 g, 237.22 mmoL) were takendioxane (100 mL) and heated at 110° C. for 4 hrs. The reaction mixturewas cooled to room temperature and filtered to remove magnesiumcarbonate. The solvent was evaporated to dryness and the residue wastaken in ether (200 mL) and washed successively with 0.5 M NaOH solution(200 mL×2) and saturated brine solution (100 mL) and dried over Na₂SO₄.It was filtered and evaporated to give4-methyl-5-(ethoxycarbonyl)thiazole as an oil which was purified bysilica gel column chromatography using hexanes:EtOAc (8:2, v/v) as aeluent; yield: 3.28 g (17%).

4-Methyl-5-(hydroxymethyl)thiazole

A 250-mL, three necked round-bottomed flask fitted with a 100-mLdropping funnel, a nitrogen-inlet tube, and a reflux condenser was addedlithium aluminum hydride (1 g, 26.35 mmol) and anhydrous ether (50 mL).To the dropping funnel was added 4-methyl-5-(ethoxycarbonyl)-thiazole (3g, 17.3 mmol) and anhydrous ether (25 mL). While the suspension oflithium aluminum hydride was gently stirred under a nitrogen atmosphere,the solution of 4-methyl-5-(ethoxycarbonyl)thiazole was added dropwiseat a rate maintaining a gentle reflux. When the addition was complete,the mixture was heated at reflux for 4 hrs. After the mixture hadreturned to room temperature, anhydrous ether (100 mL) was added. Thegray reaction mixture was hydrolyzed by addition, in small parts, of asufficient amount of wet sodium sulfate. The reaction mixture wasfiltered through a sintered-glass funnel. The organic layer separatedand dried over Na₂SO₄. It was filtered and evaporated to give desiredcompound as an oil; yield: 590 mg (26%).

3-(2-Phenyl-2-oxoethyl)-4-methyl-5-(hydroxymethyl)thiazolium Chloride

The neat reaction of 4-methyl-5-(hydroxymethyl)thiazole (590 mg, 4.57mmol) and 2-chloroacetophenone (710 mg, 4.59 mmol) was heated at 110° C.The mixture solidified within 15 minutes. Acetonitrile (10 mL) was addedand the mixture refluxed for another 3 hrs. It was cooled to roomtemperature and tert-butyl methyl ether (5 mL) was added and thereaction mixture was left overnight at room temperature. The productcrystallized was filtered and washed well with a mixture ofhexanes:EtOAc (1:1, v/v) and dried. It was recrystallized from a mixtureof actonitrile/ethanol/tert-butyl methyl ether; yield 130 mg (10%); mp.240-242° C. (dec.).

Example 63-[2-(Disubstituted-dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazoliumBromide 2-Bromo-2′,4′-dihydroxyacetophenone

Copper (II) bromide (6 g, 26.9 mmol) was suspended in ethyl acetate (50mL) and 2′,4′-dihyroxyacetophenone (2 g, 13.1 mmol) dissolved inchloroform (20 mL) was added to the suspension. The reaction mixture wasrefluxed for 8 hrs. and filtered hot through celite pad. The filtratewas evaporated to dryness to give crude oil (3.0 g, 96%). The NMRspectrum and TLC [silica gel, Hexanes:EtOAc (1:1, v/v)] was in agreementwith the desired product. It was used as such in the next step of thereaction without further purification.

This method was used to prepare:

(i) 2-Bromo-3′,5′-dihydroxyacetophenone from 3′,5′-dihydroxyacetophenoneand copper (II) bromide.(ii) 2-Bromo-2′,5′-dihydroxyacetophenone from2′,5′-dihydroxyacetophenone and copper (II) bromide. Yield: 2.99 g; 99%

3-[2-(2,4-Dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazolium Bromide

The neat mixture of 2-bromo-2′,4′-dihydroxyacetophenone (3 g, 13 mmol)and 4,5-dimethylthiazole (1.71 g, 13.3 mmol) was heated at 110° C. for 3hrs. It was dissolved in acetonitrile (15 mL) and cooled to roomtemperature. Tert-butyl methyl ether (5 mL) was added and the reactionmixture kept at room temperature overnight. The product crystallized wasfiltered, washed well with a mixture of acetonitrile and tert-butylmethyl ether (1:1, v/v) and dried. It was recrystallized from a mixtureof methanol and a few drops of water. Yield: 2.5 g (50%); mp. 257-260°C. (dec.).

This method was used to prepare:

(i) 3-[2-(3,5-Dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazoliumbromide in 55% yield from 2-bromo-3′,5′-dihydroxyacetophenone and4,5-dimethylthiazole; mp. 257-258° C. Yield: 2.05 g (21%).(ii) 3-[2-(2,5-Dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazoliumbromide in 57% yield from 2-bromo-2,5-dihydroxyacetophenone and4,5-dimethylthiazole; mp. 231-232° C. Yield: 4.03 g (52%).(iii) 3-[2-(3,4-Dihydroxyphenyl)-2-oxoethyl]-4,5-dimethylthiazoliumchloride in 60% yield from commercially available2-chloro-3′,4′-dihydroxyacetophenone and 4,5-dimethylthiazole; mp.260-263° C. (dec.); yield: 3.9 g (48%).

Example 7 Preparation of 1-methyl-3-(cyanomethyl)imidazolium Bromide

A mixture of 1-methylimidazole (1 g, 12.2 mmol) and bromoacetonitrile(1.46 g, 12.2 mmol) were combined and stirred. An exothermic reactionwas produced and the product precipitated from the reaction mixture.After cooling the reaction mixture is allowed to cool to roomtemperature acetonitrile (CH₃CN) (2 mL) is added. The crude product isrecovered by filtration and washed with additional CH₃CN. The crudeproduct is dissolved in H₂O, treated with decolorizing carbon andevaporated in vacuo to dryness. The product is further purified byrecrystallization from a mixture of ethanol EtOH, CH₃CN and diethylether to yield 1-methyl-3-(2-cyanomethylene)-imidazolium bromide as awhite crystalline solid: mp 165-167° C.

Example 8 Preparation of 3-(cyanomethyl)-4,5-dimethylthiazolium Bromide

A mixture of 4,5-dimethylthiazole and bromoacetonitrile were heated withstirring at 95° C. for 1 hour. The product precipitated from the mixturewithin 30 minutes. After cooling to room temperature, the product asolution of 30% v/v of diethyl ether: CH₃CN (10 mL) was added withstirring. The crude product was recovered by filtration, andrecrystallized from a mixture of EtOH and CH₃CN to yield 2.136 g of3-(cyanomethyl)-4,5-dimethylthiazolium bromide as needles: mp 184-186°C. (dec.).

Example 9 Preparation of 3-(cyanomethyl)-4,5-cyclohexenothiazoliumBromide

A mixture of thioformamide (0.8 g), 2-chlorocyclohexan-1-one (1.73 g),MgCO₃ (1.5 g) was refluxed in dioxane (12 mL) for 30 h. The reactionmixture was evaporated in vacuo, and the concentrated poured intodiethyl ether (30 mL). The resulting ethereal solution was washed with1% NaOH solution (3×15 mL). The combined NaOH solution was backextracted with diethyl ether. The ether layers were combined, washedwith saturated NaCl solution until neutral, and then dried over Na₂SO₄.The ethereal solution was evaporated in vacuo to afford 1.02 g of4,5-cyclohexenothiazole.

A mixture of 4,5-cyclohexenothiazole (1 g, 7.2 mmol) andbromoacetonitrile (0.863 g, 7.2 mmol) were heated at 120° C. for 1 h.After cooling the reaction mixture was treated with a solution of 30%diethyl ether in CH₃CN (10 mL). The product was recovered by filtrationand washed with additional 30% diethyl ether in CH₃CN. The product wasrecrystallized from a mixture of EtOH and CH₃CN to yield 0.752 g of3-(cyanomethyl)-4,5-cyclohexenothiazolium bromide as a crystallinesolid: mp 215-217° C. (dec.).

The preparation of 3-(2-cyanomethyl)-4,5-cyclopentenothiazolium bromidefrom 2-chlorocyclopentan-1-one is conducted as in the above procedure.

Example 10 Preparation of3-[2-(1-pyrrolidinyl)-2-oxoethyl]-1,2-dimethylimidazolium ChlorideN-(chloroacetyl)pyrrolidine

Pyrrolidine (63.9 g, 0.9 mole) was taken up in CH₂Cl₂ (640 mL) andcooled to 0° C. in a salt-ice water bath. To the stirred mixture wasadded chloroacetyl chloride (101.8 g in 450 mL of CH₂Cl₂, 0.9 mole)dropwise maintaining the internal temperature below 15° C. After addingthe chloroacetyl chloride, the mixture was stirred for one hour at 5° C.Sodium hydroxide solution (7 M, 190 mL) was added with vigorous stirringsuch that the inside temperature did not exceed 20° C. The mixture wasstirred for 15 minutes and the aqueous layer was separated. The organiclayer was washed with saturated sodium bicarbonate solution (2×200 mL),water (1×200 mL) and dried over anhydrous sodium sulfate. The solventwas removed in vacuo and the residue was recrystallized from hexane togive 64.5 g (48.6% yield) of white plate crystals; mp 43° C.

3-[2-(1-pyrrolidinyl)-2-oxoethyl]-1,2-dimethylimidazolium Chloride

A mixture of N-(chloroacetyl)pyrrolidine (2.0 g, 13.55 mmol) and1,2-dimethylimidazole (1.3 g, 13.5 mmol) were heated neat at 110° C. for3 hours. To the reaction mixture was added acetonitrile (5 mL), andheating was continued for 20 minutes. Tert-butyl methylether (10 mL) wasadded, and the resulting mixture was allowed to stand at roomtemperature overnight. The product was recovered by filtration, andwashed with a mixture of tert-butyl methyl ether and acetonitrile (7:3v/v, 50 mL). The crude product was recrystallized from a mixture ofacetonitrile and tert-butyl methyl ether to obtain 1.23 g (41%) of awhite solid; mp 191-193° C.

Example 11 Preparation of 1-butyl-3-aminoimidazolium MesityleneSulfonate

An ice-cold solution of 1-butylimidazole (7.0 g, 16.30 mmol) inanhydrous CH₂Cl₂ (35 mL) was treated dropwise with a solution ofO-mesitylene sulfonylhydroxylamine (17.8 g, 16.50 mmol) in CH₂Cl₂ (70mL). After stirring for 6 hours in the ice-bath, ether (210 mL) wasadded with stirring over the course of 1 hour. The resulting mixture wasallowed to stand at −16° C. overnight. The product was recovered byfiltration, and washed with a mixture of CH₂Cl₂:ether (3:1 v/v) to yielda white amorphous powder; 16.70 g. The crude product was recrystallizedfrom a mixture of CH₂Cl₂ (80 mL) and ether (80 mL) to give 12.40 g; mp71-73° C.

DEFINITION

Heterocycle. Except where heteroaryl is separately recited for the samesubstituent, the term “heterocycle” includes heteroaryl.

All publications and references, including but not limited to patentsand patent applications, cited in this specification are hereinincorporated by reference in their entirety as if each individualpublication or reference were specifically and individually indicated tobe incorporated by reference herein as being fully set forth. Any patentapplication to which this application claims priority is alsoincorporated by reference herein in its entirety in the manner describedabove for publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

1. A method of treating or ameliorating diabetic nephropathy in ansubject in need thereof, comprising administering a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof the formula I:

wherein R¹ and R² are (a) independently selected from hydrogen,acyloxyalkyl, alkenyl, alkyl, amino, (C₂-C₆)hydroxyalkyl, and Ar,wherein Ar is C₆ or C₁₀ aryl; or (b) together with their ring carbons R¹and R² form a C₆- or C₁₀-aromatic fused ring system; or (c) togetherwith their ring carbons R¹ and R² form a C₅-C₇ fused cycloalkyl ringhaving up to two double bonds including the fused double bond of the-olium or -onium containing ring, which cycloalkyl ring can besubstituted by one or more of the group consisting of alkyl,alkoxycarbonyl, amino, aminocarbonyl, carboxy, fluoro, or oxosubstituents; Z is (a) hydrogen, or alkyl; or (b) or a group of theformula —NR³R⁴; wherein R³ and R⁴ are hydrogen; Y is (a) amino, or (b) agroup of the formula —CH(R⁵)—R⁶ wherein R⁵ is hydrogen or alkyl-; R⁶ is(a) hydrogen, alkyl, wherein alkyl is optionally substituted withalkoxycarbonyl, alkynyl, or Rs, wherein Rs is a C₆ or C₁₀ aryl or aheterocycle containing 4-10 ring atoms of which 1-3 are heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur; or(b) a group of the formula —W—R⁷, wherein R⁷ is alkyl, alkoxy, hydroxyor Rs, wherein W is —C(═O)—; (c) a group of the formula —CH(OH)Rs; or(d) a group of the formula —W—N(R⁹)R¹⁰, wherein [a] R⁹ is hydrogen andR¹⁰ is alkyl or cycloalkyl, optionally substituted with (i) [C₆ orC₁₀]aryl, or (ii) a 5- or 6-membered heteroaryl ring, wherein the6-membered heteroaryl ring contains one to three atoms of N, and the5-membered heteroaryl ring contains from one to three atoms of N or oneatom of O or S and zero to two atoms of N, said heteroaryl ring can beoptionally substituted with one or more 1-pyrrolidinyl, 4-[C₆ orC₁₀]arylpiperazin-1-yl, 4-[C₆ or C₁₀]arylpiperidin-1-yl, azetidin-1-yl,and morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or (C₁-C₃)alkylenedioxy groups, or fused to a substituted phenyl or pyridine ring,wherein the ring fusion is at a carbon-carbon double bond of theheteroaryl ring, or (iii) a heterocycle containing 4-10 ring atoms ofwhich 1-3 are heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur; or [b] R⁹ is hydrogen and R¹⁰ is Ar; or [c] R⁹ andR¹⁰ are both alkyl groups; or [d] R⁹ and R¹⁰ together with N form aheterocycle containing 4-10 ring atoms which can incorporate up to oneadditional heteroatom selected from the group of N, O or S in the ring,wherein the heterocycle is optionally substituted with (C₆- or C₁₀)aryl,(C₆- or C₁₀)arylalkyl, or a 5- or 6-membered heteroaryl ring, whereinthe 6-membered heteroaryl ring contains one to three atoms of N, and the5-membered heteroaryl ring contains from one to three atoms of N or oneatom of O or S and zero to two atoms of N, each such heteroaryl can beoptionally substituted with one or more 1-pyrrolidinyl, 4-[C₆ orC₁₀]arylpiperazin-1-yl, 4-[C₆ or C₁₀] arylpiperidin-1-yl, azetidin-1-yl,morpholin-4-yl, thiomorpholin-4-yl, piperidin-1-yl, halo or(C₁-C₃)alkylenedioxy; or [f] R⁹ and R¹⁰ are both hydrogen; Q is S; M isabsent; X is a pharmaceutically acceptable anion, or a pharmaceuticallyacceptable salt of the compound, wherein aryl or Ar is optionallysubstituted with, in addition to any substitutions specifically noted,one or more substituents selected from the group consisting ofacylamino, acyloxyalkyl, alkanoyl, alkanoylalkyl, alkenyl, alkoxy,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino,(C₁-C₃)alkylenedioxy, alkylsulfonyl, alkylsulfinyl, ω-alkylenesulfonicacid, alkylthio, allyl, amino, ArC(O)—, ArC(O)NH—, ArO—, Ar—, Ar-alkyl-,carboxy, carboxyalkyl, cycloalkyl, dialkylamino, halo, trifluoromethyl,hydroxy, (C₂-C₆)hydroxyalkyl, mercapto, nitro, sulfamoyl, sulfonic acid,1-pyrrolidinyl, 4-[C₆ or C₁₀]arylpiperazin-1-yl, 4-[C₆ orC₁₀]arylpiperidin-1-yl, azetidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperidin-1-yl; and wherein heterocycle, exceptthose of Ar, is optionally substituted with, in addition to anysubstitutions specifically noted, acylamino, alkanoyl, alkoxy,alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylsulfonyl,alkylsulfinyl, alkylthio, amino, ArC(O)—, ArO—, Ar—, carboxy,dialkylamino, fluoro, fluoroalkyl, difluoroalkyl, hydroxy, mercapto,sulfamoyl, or trifluoromethyl; and a pharmaceutically acceptablecarrier, thereby treating or ameliorating said diabetic nephropathy. 2.The method of claim 1, comprising administering a compound, wherein R¹and R² are both alkyl.
 3. The method of claim 2, wherein alkyl ismethyl.
 4. The method of claim 1, comprising administering a compound,wherein Z is hydrogen.
 5. The method of claim 1, comprisingadministering a compound, wherein Y is —CH₂—C(═O)—Rs.
 6. The method ofclaim 5, comprising administering a compound, wherein Rs is C₆ aryl. 7.The method of claim 1, wherein the compound is3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium salt.
 8. The method ofclaim 7, wherein the compound is3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium chloride.
 9. The methodof claim 7, wherein the compound is3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide.
 10. The methodof claim 1, wherein the diabetic nephropathy is associated withdiabetes.
 11. The method of claim 1, wherein the diabetic nephropathy isassociated with albuminuria.
 12. The method of claim 1, wherein thetreatment or amelioration of said diabetic nephropathy, breaks, reducesor inhibits the formation of advanced glycoslyation end products oradvanced glycoslyation end product-mediated crosslinks.
 13. The methodof claim 1, wherein said subject is a mammal.
 14. The method of claim13, wherein said mammal is a human.
 15. The method of claim 1, whereinthe pharmaceutical composition is administered via oral, parenteral,sublingual, buccal, rectal, nasal, inhalation, ocular, vaginal, topical,pulmonary, intramuscular, subcutaneous, intraperitoneal, intraarterial,intravenous or intrathecal routes.
 16. The method of claim 15, whereinthe pharmaceutical composition is administered orally as a tablet,chewable tablet, capsule, or lozenge.
 17. The method of claim 1, whereinthe therapeutically effective amount is from about 0.7 mg to about 280mg daily.
 18. The method of claim 1, wherein the therapeuticallyeffective amount is from about 0.5 mg to about 210 mg daily.
 19. Themethod of claim 1, wherein the therapeutically effective amount is 0.1mg/kg to 4 mg/kg body weight daily.
 20. The method of claim 19, whereinthe therapeutically effective amount is 1 mg/kg body weight daily.